Pyridine compounds

ABSTRACT

This invention features compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     pharmaceutical compositions of the compounds, and methods of using the compounds for the treatment of, inter alia, IL-12-related diseases and disorders.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/985,696, filed Nov. 10, 2004, allowed, which claims the benefit ofU.S. Provisional Patent Application Nos. 60/518,791, filed Nov. 10,2003, and 60/585,124, filed Jul. 1, 2004. The contents of each of theseapplications are hereby incorporated by reference in their entirety.

BACKGROUND

Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) which plays keyroles in immune responses by bridging innate resistance andantigen-specific adaptive immunity. Trinchieri (1993) Immunol Today 14:335. For example, it promotes type 1 T helper cell (T_(H)1) responsesand, hence, cell-mediated immunity. Chan et al. (1991) J Exp Med 173:869; Seder et al. (1993) Proc Natl Acad Sci USA 90: 10188; Manetti etal. (1993) J Exp Med 177: 1199; and Hsieh et al. (1993) Science 260:547. Interleukin-12 (IL-12) is a di-sulfide linked heterodimericcytokine (p70) composed of two independently regulated subunits, p35 andp40. IL-12 is produced by phagocytic cells and antigen presenting cells,in particular, macrophages and dendritic cells, upon stimulation withbacteria, bacterial products such as lipopolysaccharide (LPS), andintracellular parasites. The well-documented biological functions ofIL-12 are induction of interferon-γ expression from T and NK cells anddifferentiation toward the T_(H)1 T lymphocyte type. IFN-γ, expressionof which is induced by IL-12, is a strong and selective enhancer ofIL-12 production from monocytes and macrophages. The cytokine IL-23 is aheterodimer composed of a p19 subunit and the same p40 subunit of IL-12.IL-23, similarly to IL-12, is involved in type 1 immune defenses andinduces IFN-γ secretion from T cells. IL-27 is formed by the associationof EB13, a polypeptide related to the p40 subunit of IL-12, and p28, aprotein related to the p35 subunit of IL-12. IL-27 promotes the growthof T cells and is thought to play a role in the differentiation ofT_(H)1 cells. Pflanz et al., Immunity (2002), 16:779-790.

It has been suggested that, particularly in chronic diseases in whichthere is ongoing production of IFN-γ, IL-12 production is augmented byIFN-γ. It is presumed that after an infective or inflammatory stimulusthat provokes IL-12 production, the powerful feedback loop promotesIL-12- and IL-23-induced IFN-γ to further augment IL-12 production,leading to consequent excessive production of pro-inflammatorycytokines. Furthermore, it has been suggested that IL-27 induces theexpression of T-bet, a major T_(H)1-specific transcription factor, andit's downstream target IL-12R β2, independently of IFN-γ. In addition,IL-27 suppresses the expression of GATA-3. GATA-3 inhibits T_(H)1development and causes loss of IL-12 signaling through suppression ofIL-12R β2 and Stat4 expression. Lucas et al., PNAS (2003),100:15047-15052.

IL-12 plays a critical role in multiple-T_(H)1 dominant autoimmunediseases including, but not limited to, multiple sclerosis, sepsis,myasthenia gravis, autoimmune neuropathies, Guillain-Barré syndrome,autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia,autoimmune thrombocytopenia, temporal arteritis, anti-phospholipidsyndrome, vasculitides, Wegener's granulomatosis, Behcet's disease,psoriasis, psoriatic arthritis, dermatitis herpetiformis, pemphigusvulgaris, vitiligo, Crohn's disease, ulcerative colitis, interstitialpulmonary fibrosis, myelofibrosis, hepatic fibrosis, myocarditis,thyroditis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 orimmune-mediated diabetes mellitus, Grave's disease, Hashimoto'sthyroiditis, autoimmune oophoritis and orchitis, autoimmune disease ofthe adrenal gland; rheumatoid arthritis, juvenile rheumatoid arthritis,systemic lupus erythematosus, scleroderma, polymyositis,dermatomyositis, spondyloarthropathies, ankylosing spondylitis,Sjogren's syndrome and graft-versus-host disease. See, for example,Gately et al. (1998) Annu Rev Immunol. 16: 495; and Abbas et al. (1996)Nature 383: 787.

Inhibiting IL-12 overproduction, or inhibiting the production ofcytokines such as IL-23 and IL-27 which promote IL-12 production and/orT_(H)1 development is an approach to treating the just-mentioneddiseases. Trembleau et al. (1995) Immunol. Today 16: 383; and Adorini etal. (1997) Chem. Immunol. 68: 175. For example, overproduction of IL-12and the resultant excessive T_(H)1 type responses can be suppressed bymodulating IL-12, IL-23 and/or IL-27 production. Therefore, compoundsthat down-regulate IL-12, IL-23 and/or IL-27 production can be used fortreating inflammatory diseases. Ma et al. (1998) Eur Cytokine Netw 9:54.

SUMMARY OF THE INVENTION

In one aspect, the invention features a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph or prodrug thereof. In formula (I):

-   -   R¹ is

optionally substituted aryl, or optionally substituted heteroaryl;

-   -   R₂ and R₄ are, independently, H, an optionally substituted        alkyl, an optionally substituted alkylcarbonyl, —OR^(k),        —SR^(k), —NR^(h)R^(j), hydroxylalkyl, —C(O)R^(c), —OC(O)R^(c),        —SC(O)R^(c), —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c),        —SC(S)R^(c), —NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c),        —SC(NR)R^(c), —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c),        —NR^(k)SO₂R^(c), —OS(O)₂R^(c), —OP(O)R^(c)R^(c),        —P(O)R^(c)R^(c), halo, haloalkyl, aminoalkyl, mercaptoalkyl,        cyano, nitro, nitroso, azide, an optionally substituted        alkylcarbonylalkyl, an optionally substituted cyclyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted heterocycloalkyl, an        optionally substituted aryl, an optionally substituted aralkyl,        an optionally substituted heteroaryl, an optionally substituted        heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are        ═O, ═S, or ═NR;    -   R₃ is R^(g), —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c),        —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),        —NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),        —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c),        —OS(O)₂R^(c), —OP(O)R^(c)R^(c), or —P(O)R^(c)R^(c);    -   R₅ is —H, alkyl, alkylcarbonyl, halo, nitro, nitroso, cyano,        azido, isothionitro, —OR^(p) or —SR^(p); and R^(p) is —H, alkyl,        or alkylcarbonyl; n, for each occurrence, is independently 0, 1,        2, 3, 4, 5, 6 or 7; X is O, S, S(O), S(O)₂, or NR^(k); Y is        (CH(R^(g)))_(m), C(O), C(NR), O, S, S(O), S(O)₂, N(R^(k)), or        absent; Z is N or CH; W is O, S, S(O), S(O)₂, NR^(m), or        NC(O)R^(m), wherein R^(m) is H, alkyl, aryl, heteroaryl,        cycloalkyl, heterocycloalkyl, or alkylcarbonyl.

Furthermore, in formula (I), G is: Hydrazide; Hydrazone; Hydrazine;Hydroxylamine; Oxime; Amide; Ester; Carbonate; Carbamate; Thiocarbamate;—NR^(k)—C(NR)—NR^(k)—; —NR^(k), —C(O)—NR^(k)—; —NR^(k), —C(S)—NR^(k)—;—NR^(k)—S(O)₂—NR^(k)—; Phosphoryl; optionally substituted -Cyclyl-;optionally substituted -Heterocyclyl-; optionally substituted -Aryl-;optionally substituted -Heteroaryl-; optionally substituted-Heteroarylalkyl-; optionally substituted -Heteroaryl-NR^(k)—;optionally substituted -Heteroaryl-S—; optionally substituted-Heteroarylalkyl-O—; —Si(OR^(k))₂—; —B(OR^(k))—; —C(NR)—NR^(k)—;—N(R^(k))—CR^(g)R^(g)—C(O)—; —C(O)—ON(R^(k))—; —C(O)—N(R^(k))O—;—C(S)—ON(R^(k))—; C(S)—N(R^(k))O—; —C(N(R^(k)))—ON(R^(k))—;—C(N(R^(k)))—NR^(k)O—; —OS(O)₂—N(R^(k))N(R^(k))—;—OC(O)—N(R^(k))N(R^(k))—; —OC(S)—N(R^(k))N(R^(k))—;—OC(N(R^(k)))—N(R^(k))N(R^(k))—; —N(R^(k))N(R^(k))S(O)₂O—;—N(R^(k))N(R^(k))C(S)O—; —N(R^(k))N(R^(k))C(N(R^(k)))O—;—OP(O)(R^(c))O—; —N(R^(k))P(O)(R^(c))O—; —OP(O)(R^(c))N(R^(k))—;—(R^(k))P(O)(R^(c))N(R^(k))—; —P(O)(R^(c))O—; —P(O)(R^(c))N(R^(k))—;—N(R^(k))P(O)(R^(c))—; —OP(O)(R^(c))—; —O-alkyl-heterocyclyl-N(R^(k))—;—N(R^(k))CHR^(g)C(O)N(R^(k))CHR^(g)C(O)—; —N(R^(k))CHR^(g)C(O)—;—N(R^(k))C(O)CHR^(g)—; —C(O)N(R^(k))CHR^(g)C(O)—; each of which isoptionally substituted; or G is absent; and one of Q, U and V is N, andthe other two are each CR^(g) and each CR^(g) may be the same ordifferent.

Further, in formula (I), R, for each occurrence, is independently H, anoptionally substituted alkyl, an optionally substituted cycloalkyl, anoptionally substituted cyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl,—C(O)R^(c), —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl, nitro, cyano,haloalkyl, aminoalkyl, or —S(O)₂R^(c); each of R^(a) and R^(b),independently, is H, optionally substituted alkyl, an optionallysubstituted cycloalkyl, an optionally substituted cyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; R^(c)and R^(d), for each occurrence, are independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cyclyl, an optionallysubstituted cycloalkyl, an optionally substituted heterocyclyl, anoptionally substituted heterocycloalkyl, an optionally substitutedaralkyl, an optionally substituted heteroaralkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, haloalkyl,—OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl, alkylcarbonylalkyl,mercaptoalkyl, aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy;R^(f), for each occurrence, is independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cyclyl, an optionallysubstituted cycloalkyl, an optionally substituted heterocyclyl, anoptionally substituted heterocycloalkyl, an optionally substitutedaralkyl, an optionally substituted heteroaralkyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, —C(O)R^(c),—C(S)R^(c), —C(NR)R^(c), —S(O)R^(c), —S(O)₂R^(c), —P(O)R^(c)R^(c), or—P(S)R^(c)R^(c); R^(g), for each occurrence, is independently, H, anoptionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cyclyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, anoptionally substituted aryl, an optionally substituted heteroaryl,haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl,alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl,sulfonylaryl, thioalkoxy, —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c),—NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),—NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),—NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c), —OS(O)₂R^(c),—OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo, aminoalkyl, mercaptoalkyl,cyano, nitro, nitroso, or azide; R^(h) and R^(j), for each occurrence,are independently H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl; orR^(h) and R^(j) taken together with the N to which they are attached isan optionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, or an optionally substituted heteroaryl; and R^(k),for each occurrence, is independently H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, oran optionally substituted heteroaryl.

In another aspect, this invention features a pharmaceutical compositionthat includes a pharmaceutically acceptable carrier and at least one ofthe heteroaryl compounds of this invention (e.g., a compound of formula(I) herein; any compound delineated herein).

In another aspect, the present invention features a method of inhibitingthe production of IL-12 and/or inhibiting the production of a cytokinethat stimulates or otherwise augments the production of IL-12 (e.g.,IL-23 and IL-27) and/or inhibits the proliferation of T_(H)1 lymphocytesin a subject by administering to the subject an effective amount of acompound represented by formula (I) (or any of the formulae herein) or apharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph, or prodrug thereof.

In another aspect, the invention features a method of inhibiting theproduction and/or development of T_(H)1 cells in a subject byadministering to the subject an effective amount of a compound offormula (I) (or any of the formulae herein) or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugthereof.

In another aspect, the present invention features a method for treatingan IL-12 overproduction-related disorder (e.g., multiple sclerosis,sepsis, myasthenia gravis, autoimmune neuropathies, Guillain-Barrésyndrome, autoimmune uveitis, autoimmune hemolytic anemia, perniciousanemia, autoimmune thrombocytopenia, temporal arteritis,anti-phospholipid syndrome, vasculitides, Wegener's granulomatosis,Behcet's disease, psoriasis, psoriatic arthritis, dermatitisherpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, ulcerativecolitis, interstitial pulmonary fibrosis, myelofibrosis, hepaticfibrosis, myocarditis, thyroditis, primary biliary cirrhosis, autoimmunehepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease,Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmunedisease of the adrenal gland; rheumatoid arthritis, juvenile rheumatoidarthritis, systemic lupus erythematosus, scleroderma, polymyositis,dermatomyositis, spondyloarthropathies, ankylosing spondylitis,Sjogren's syndrome and graft-versus-host disease). The method includesadministering to a subject (e.g., a human or an animal) in need thereofan effective amount of one or more heteroaryl compounds of thisinvention. The method can also include the step of identifying a subjectin need of treatment of diseases or disorders described above. Theidentification can be in the judgment of a subject or a healthprofessional and can be subjective (e.g., opinion) or objective (e.g.,measurable by a test or a diagnostic method).

The methods herein also include those wherein the subject administeredthe compound or composition herein is treated, including as identifiedas being treated for an IL-12 overproduction disorder.

Also within the scope of this invention are compositions containing oneor more of the compounds described above for use in treating an IL-12overproduction-related disorder, and the use of such a composition forthe manufacture of a medicament for the just-described use.

Other features, objects, and advantages of the invention will beapparent from the description and from the claims.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of a compound of the invention inan in vivo arthritis model.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph or prodrug thereof. In formula (I):

-   -   R¹ is

optionally substituted aryl, or optionally substituted heteroaryl;

-   -   R₂ and R₄ are, independently, H, an optionally substituted        alkyl, an optionally substituted alkylcarbonyl, —OR^(k),        —SR^(k), —NR^(h)R^(j), hydroxylalkyl, —C(O)R^(c), —OC(O)R^(c),        —SC(O)R^(c), —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c),        —SC(S)R^(c), —NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c),        —SC(NR)R^(c), —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c),        —NR^(k)SO₂R^(c), —OS(O)₂R^(c), —OP(O)R^(c)R^(c),        —P(O)R^(c)R^(c), halo, haloalkyl, aminoalkyl, mercaptoalkyl,        cyano, nitro, nitroso, azide, an optionally substituted        alkylcarbonylalkyl, an optionally substituted cyclyl, an        optionally substituted cycloalkyl, an optionally substituted        heterocyclyl, an optionally substituted heterocycloalkyl, an        optionally substituted aryl, an optionally substituted aralkyl,        an optionally substituted heteroaryl, an optionally substituted        heteroaralkyl, or isothionitro; or R₂ and R₄ taken together are        ═O, ═S, or ═NR;    -   R₃ is R^(g), —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c),        —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),        —NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),        —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c),        —OS(O)₂R^(c), —OP(O)R^(c)R^(c), or —P(O)R^(c)R^(c);    -   R₅ is —H, alkyl, alkylcarbonyl, halo, nitro, nitroso, cyano,        azido, isothionitro, —OR^(p) or —SR^(p); and R^(p) is —H, alkyl,        or alkylcarbonyl; n, for each occurrence, is independently 0, 1,        2, 3, 4, 5, 6 or 7; X is O, S, S(O), S(O)₂, or NR^(k); Y is        (CH(R^(g)))_(m), C(O), C(NR), O, S, S(O), S(O)₂, N(R^(k)), or        absent; Z is N or CH; W is O, S, S(O), S(O)₂, NR^(m), or        NC(O)R^(m), wherein R^(m) is H, alkyl, aryl, heteroaryl,        cycloalkyl, heterocycloalkyl, or alkylcarbonyl.

Furthermore, in formula (I), G is: Hydrazide (e.g., —C(O)NHN(R^(k))— or—N(R^(k))NHC(O)—); Hydrazone (e.g., —C(R^(g))═N—N(R^(k))— or>C═N—NR^(h)R^(j) or —N(R^(k))—N═C(R^(g))—); Hydrazine (e.g.,—N(R^(k))—N(R^(k))—); Hydroxylamine (i.e., —N(OH)—); Oxime (i.e.,—C(N—OH)—); Amide; Ester; Carbonate (—OC(O)O—); Carbamate (e.g.,—OC(O)N(R^(k))— or —N(R^(k))C(O)O—); Thiocarbamate (e.g.,—OC(S)N(R^(k))— or —N(R^(k))C(S)O— or —SC(O)N(R^(k))— or—N(R^(k))C(O)S—); —NR^(k)—C(NR)—NR^(k)—; —NR^(k)— C(O)—NR^(k)—;—NR^(k)—C(S)—NR^(k)—; —NR^(k)—S(O)₂—NR^(k)—; Phosphoryl; optionallysubstituted -Cyclyl-; optionally substituted -Heterocyclyl-; optionallysubstituted -Aryl-; optionally substituted -Heteroaryl-; optionallysubstituted -Heteroarylalkyl-; optionally substituted-Heteroaryl-NR^(k)—; optionally substituted -Heteroaryl-S—; optionallysubstituted -Heteroarylalkyl-O—; —Si(OR^(k))₂—; —B(OR^(k))—;—C(NR)—NR^(k)—; —N(R^(k))—CR^(g)R^(g)—C(O)—; —C(O)—ON(R^(k))—;—C(O)—N(R^(k))O—; —C(S)—ON(R^(k))—; C(S)—N(R^(k))O—;—C(N(R^(k)))—ON(R^(k))—; —C(N(R^(k)))—NR^(k)O—;—OS(O)₂—N(R^(k))N(R^(k))—; —OC(O)—N(R^(k))N(R^(k))—;—OC(S)—N(R^(k))N(R^(k))—; —OC(N(R^(k)))—N(R^(k))N(R^(k))—;—N(R^(k))N(R^(k))S(O)₂O—; —N(R^(k))N(R^(k))C(S)O—;—N(R^(k))N(R^(k))C(N(R^(k)))O—; —OP(O)(R^(c))O—; —N(R^(k))P(O)(R^(c))O—;—OP(O)(R^(c))N(R^(k))—; —(R^(k))P(O)(R^(c))N(R^(k))—; —P(O)(R^(c))O—;—P(O)(R^(c))N(R^(k))—; —N(R^(k))P(O)(R^(c))—; —OP(O)(R^(c))—;—O-alkyl-heterocyclyl-N(R^(k))—;—N(R^(k))CHR^(g)C(O)N(R^(k))CHR^(g)C(O)—; —N(R^(k))CHR^(g)C(O)—;—N(R^(k))C(O)CHR^(g)—; —C(O)N(R^(k))CHR^(g)C(O)—; each of which isoptionally substituted; or G is absent; and one of Q, U and V is N, andthe other two are each CR^(g) and each CR^(g) may be the same ordifferent.

Further, in formula (I), R, for each occurrence, is independently H, anoptionally substituted alkyl, an optionally substituted cycloalkyl, anoptionally substituted cyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, —C(O)R^(c), OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, nitro, cyano, haloalkyl, aminoalkyl, or —S(O)₂R^(c); eachof R^(a) and R^(b), independently, is H, optionally substituted alkyl,an optionally substituted cycloalkyl, an optionally substituted cyclyl,an optionally substituted heterocycloalkyl, an optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; R^(c) and R^(d), for each occurrence, are independently, H,an optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cyclyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, anoptionally substituted aryl, an optionally substituted heteroaryl,haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl,alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl,sulfonylaryl, or thioalkoxy; R^(f), for each occurrence, isindependently, H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl,—C(O)R^(c), —C(S)R^(c), —C(NR)R^(c), —S(O)R^(c), —S(O)₂R^(c),—P(O)R^(c)R^(c), or —P(S)R^(c)R^(c); R^(g) for each occurrence, isindependently, H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl,haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl,alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl, sulfonylalkyl,sulfonylaryl, thioalkoxy, —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c),—NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),—NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),—NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c), —OS(O)₂R^(c),—OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo, aminoalkyl, mercaptoalkyl,cyano, nitro, nitroso, or azide; R^(h) and R^(j), for each occurrence,are independently H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl; orR^(h) and R^(j) taken together with the N to which they are attached isan optionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, or an optionally substituted heteroaryl; and R^(k),for each occurrence, is independently H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, oran optionally substituted heteroaryl.

In preferred embodiments: R¹ is

more preferably in which one of Q, U and V is N, and the other two areCR^(g), wherein each R^(g) is, independently selected from the groupconsisting of H, F, Cl, CN, a lower alkyl, a lower haloalkyl, a loweralkoxy, a lower haloalkoxy, a lower alkylamino, a lower dialkylamino, alower aminoalkyl, and —NH₂. More preferably, one of Q, U and V is N, andthe other two are independently selected from the group consisting ofCH, CF, C(CN), CCl, C(CH₃), C(OCH₃), C(OCF₃), and C(CF₃), morepreferably one of Q, U and V is N, and the other two are independentlyselected from the group consisting of CH and CF. In preferredembodiments, U is N and Q and V each are CH. In preferred embodiments, Zis N and W is O; in preferred embodiments, X is O or NR^(k). Inpreferred embodiments, Y is a covalent bond, O, S, or CH₂, and n is 0,1, 2, 3, or 4. In preferred embodiments, G is >C═N—R (e.g., an imine oroxime), —NR^(k)C(O)—, —C(O)NR^(k), —OC(O)—, —C(O)O—, —OC(O)O—,—NR^(k)C(O)O—, —OC(O)NR^(k)—, —NR^(k)C(S)O—, —OC(S)NR^(k)—,—NR^(k)C(NR)NR^(k)—, —NR^(k)C(O)NR^(k)—, —NR^(k)C(S)NR^(k)—,—NR^(k)S(O)₂NR^(k)—, —C(NR)NR^(k)—, or —NR^(k) CR^(g)R^(g)C(O)—. Inpreferred embodiments, R₃ is an optionally substituted alkyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted cycloalkyl, an optionally substituted cyclyl, anoptionally substituted heterocycloalkyl, an optionally substitutedheterocyclyl, nitro, cyano, halo, OR^(k), SR^(k) or NR^(h)R^(j), morepreferably optionally substituted aryl or optionally substitutedheteroaryl. In preferred embodiments, R₃ is an optionally substitutedphenyl, an optionally substituted naphthyl, an optionally substitutedanthracenyl, an optionally substituted fluorenyl, an optionallysubstituted indenyl, an optionally substituted azulenyl, an optionallysubstituted pyridyl, an optionally substituted 1-oxo-pyridyl, anoptionally substituted furanyl, an optionally substitutedbenzo[1,3]dioxolyl, an optionally substituted benzo[1,4]dioxinyl, anoptionally substituted thienyl, an optionally substituted pyrrolyl, anoptionally substituted oxazolyl, an optionally substituted imidazolyl,an optionally substituted thiazolyl, an optionally substitutedisoxazolyl, an optionally substituted quinolinyl, an optionallysubstituted pyrazolyl, an optionally substituted isothiazolyl, anoptionally substituted pyridazinyl, an optionally substitutedpyrimidinyl, an optionally substituted pyrazinyl, an optionallysubstituted triazinyl, an optionally substituted triazolyl, anoptionally substituted thiadiazolyl, an optionally substitutedisoquinolinyl, an optionally substituted indazolyl, an optionallysubstituted benzoxazolyl, an optionally substituted benzofuryl, anoptionally substituted indolizinyl, an optionally substitutedimidazopyridyl, an optionally substituted tetrazolyl, an optionallysubstituted benzimidazolyl, an optionally substituted benzothiazolyl, anoptionally substituted benzothiadiazolyl, an optionally substitutedbenzoxadiazolyl, an optionally substituted indolyl, an optionallysubstituted tetrahydroindolyl, an optionally substituted azaindolyl, anoptionally substituted indazolyl, an optionally substitutedimidazopyridyl, an optionally substituted quinazolinyl, an optionallysubstituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl,an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionallysubstituted benzo[b]thienyl. In other preferred embodiments, R₃ is anoptionally substituted heterocycloalkyl. In preferred embodiments, R₃ isan optionally substituted piperidinyl, an optionally substitutedpiperazinyl, an optionally substituted 2-oxopiperazinyl, an optionallysubstituted 2-oxopiperidinyl, an optionally substituted2-oxopyrrolidinyl, an optionally substituted 4-piperidonyl, anoptionally substituted tetrahydropyranyl, an optionally substitutedoxazolidinyl, an optionally substituted 2-oxo-oxazolidinyl, anoptionally substituted tetrahydrothiopyranyl, an optionally substitutedtetrahydrothiopyranyl sulfone, an optionally substituted morpholinyl, anoptionally substituted thiomorpholinyl, an optionally substitutedthiomorpholinyl sulfoxide, an optionally substituted thiomorpholinylsulfone, an optionally substituted 1,3-dioxolanyl, an optionallysubstituted[1,4]dioxanyl, an optionally substituted2-oxo-imidazolidinyl, tetrahydrofuranyl, or an optionally substitutedtetrahydrothienyl. In preferred embodiments, R₃ is —OR^(k) or—NR^(h)R^(j), and R^(f), R^(h) and R^(j) are each, independently, H oralkyl. In certain preferred embodiments, R₃ is

in which each of A and A′, independently, is O, S, NH or NR^(y), whereinR^(y) is lower alkyl; each of R^(e) and R^(e′), independently is H,optionally substituted alkyl, substituted aryl, or substitutedheteroaryl; and m is 1 or 2. In certain preferred embodiments, R₃ is—C(O)OR^(k), —OC(O)R^(k), —C(O)NR^(h)R^(j), —NR^(k)C(O)R^(k),—C(S)OR^(k), —OC(S)R^(k), —NR^(k)C(O)NR^(h)R^(j),—NR^(k)C(S)NR^(h)R^(j), —C(O)NRhRj, —S(O)₂R^(k), —S(O)₂NR^(h)R^(j),—OC(O)NR^(h)R^(j), or —NR^(k)C(O)OR^(k).

In certain embodiments of the compounds of Formula (I), one of R^(a) orR^(b) is an optionally substituted aryl or an optionally substitutedheteroaryl. In certain preferred embodiments, one of R^(a) and R^(b) is

in which A₁ is NR^(i), O, or S; A₂ is N or CR^(i); R^(q) is H, halogen,CN, optionally substituted alkyl, optionally substituted cyclyl,optionally substituted alkyloxy, optionally substituted alkylcarbonyl,optionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl, optionally substituted heteroaryloxycarbonyl,hydroxyalkyl, alkylamino, or alkylaminocarbonyl; each R^(r) is,independently, H, halogen, NO₂, CN, optionally substituted alkyl,optionally substituted aryl, optionally substituted heteroaryl, OR^(k),OC(O)R^(k), SO₂R^(k), S(O)R^(k), S(O₂)NR^(h)R^(j), SR^(k), NR^(h)R^(j),NR^(k)COR^(k), NR^(k)C(O)OR^(k), NR^(k)C(O)NR^(h)R^(j), NR^(k)SO₂R^(k),COR^(k), C(O)OR^(k), or C(O)NR^(h)R^(j); R^(i) is H, optionallysubstituted alkyl, or optionally substituted alkylcarbonyl; y is 0, 1,or 2; and z is 0, 1, 2, 3, or 4. In further preferred embodiments, oneof R^(a) and R^(b) is

and the other of R^(a) and R^(b) is H or alkyl. In certain preferredembodiments, R^(q) is H, methyl, ethyl, propyl, cyclopropyl, methoxy,ethoxy, methoxycarbonyl, or halogen; each R^(r) is, independently, F,Cl, CN, methyl, methoxy, ethoxy, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCH₂CH₃,—N(CH₂CH₃)₂, OC(O)CH₃, OC(O)C₂H₅, C(O)OH, C(O)OC₂H₅, C(O)NH₂, NHC(O)CH₃,or S(O₂)NH₂; R^(i) is H, methyl, ethyl, or acetyl, and z is 0, 1, or 2.In preferred embodiments, one of Q, U and V is N, and the other two areeach CH, and more preferably, U is N, Q and V are each CH, Z is N, and Wis O; in still more preferred embodiments, X is NR^(k); and R^(k) is H,methyl, ethyl, or acetyl, and yet more preferably, Y is a covalent bond,O, S, or NH, N(CH₃), CH₂; and n is 0, 1, 2, 3, or 4; still morepreferably, R₃ is R^(k), nitro, cyano, halo, OR^(k), SR^(k), C(O)R^(k),C(O)OR^(k), or C(O)NR^(h)R^(j). In other preferred embodiments, Q is N,U and V are each CH, Z is N, and W is O; or V is N, Q and U are each CH,Z is N, and W is O.

In certain preferred embodiments of the compounds of formula (I), R₁ isoptionally substituted aryl or optionally substituted heteroaryl; morepreferably in these embodiments, G is >C═N—R, —NR^(k)C(O)—,—C(O)NR^(k)—, —OC(O)—, —C(O)O—, —OC(O)O—, —NR^(k)C(O)O—, —OC(O)NR^(k)—,—NR^(k)C(S)O—, —OC(S)NR^(k)—, —NR^(k)C(NR)NR^(k)—, —NR^(k)C(O)NR^(k)—,—NR^(k)C(S)NR^(k)—, —NR^(k)S(O)₂NR^(k)—, —C(NR)NR^(k)—, or—NR^(k)CR^(g)R^(g)C(O)—. In certain embodiments, R_(j) is

in which D is O, S, or NR^(t); each R^(s) is, independently, phenyl,halogen, CN, hydroxyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkoxyl, optionally substituted aryloxyl, or optionallysubstituted heteroaryloxyl; R^(t) is H, alkyl, or alkylcarbonyl; and yis 0, 1, or 2; in preferred embodiments, X is NR^(k) in which R^(k) isH, methyl, ethyl, or acetyl.

In certain embodiments of Formula (I) in which R₁ is optionallysubstituted aryl or optionally substituted heteroaryl, G ispreferably >C═N—R, —NR^(k)C(O)—, —C(O)NR^(k)—, —OC(O)—, —C(O)O—,—OC(O)O—, —NR^(k)C(O)O—, —OC(O)NR^(k)—, —NR^(k)C(S)O—, —OC(S)NR^(k)—,—NR^(k)C(NR)NR^(k)—, —NR^(k)C(O)NR^(k)—, —NR^(k)C(S)NR^(k)—,—NR^(k)S(O)₂NR^(k)—, —C(NR)NR^(k)—, or —NR^(k)CR^(g)R^(g)C(O)—. Incertain embodiments of Formula (I) in which R₁ is aryl or heteroaryl, R₁is

wherein D is O, S, or NR^(t); each R^(s) is, independently, phenyl,halogen, CN, hydroxyl, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkoxyl, optionally substituted aryloxyl, or optionallysubstituted heteroaryloxyl; R^(t) is H, alkyl, or alkylcarbonyl; and yis 0, 1, or 2; in preferred embodiments, X is NR^(k); and R^(k) is H,methyl, ethyl, or acetyl.

In certain embodiments of Formula (I) in which R₁ is optionallysubstituted aryl or optionally substituted heteroaryl, one of Q, U and Vis N, and the other two are each CH; more preferably, Q is N, U and Vare each CH, Z is N, and W is O; or V is N, Q and U are each CH, Z is N,and W is O; or U is N, Q and V are each CH, Z is N, and W is O, and morepreferably, Y is a covalent bond, O, S, NH, N(CH₃) or CH₂, and n is 0,1, 2, 3, or 4; more preferably, R₃ is optionally substituted aryl oroptionally substituted heteroaryl; still more preferably, R₃ is anoptionally substituted phenyl, an optionally substituted naphthyl, anoptionally substituted anthracenyl, an optionally substituted fluorenyl,an optionally substituted indenyl, an optionally substituted azulenyl,an optionally substituted pyridyl, an optionally substituted1-oxo-pyridyl, an optionally substituted furanyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substitutedbenzo[1,4]dioxinyl, an optionally substituted thienyl, an optionallysubstituted pyrrolyl, an optionally substituted oxazolyl, an optionallysubstituted imidazolyl, an optionally substituted thiazolyl, anoptionally substituted isoxazolyl, an optionally substituted quinolinyl,an optionally substituted pyrazolyl, an optionally substitutedisothiazolyl, an optionally substituted pyridazinyl, an optionallysubstituted pyrimidinyl, an optionally substituted pyrazinyl, anoptionally substituted triazinyl, an optionally substituted triazolyl,an optionally substituted thiadiazolyl, an optionally substitutedisoquinolinyl, an optionally substituted indazolyl, an optionallysubstituted benzoxazolyl, an optionally substituted benzofuryl, anoptionally substituted indolizinyl, an optionally substitutedimidazopyridyl, an optionally substituted tetrazolyl, an optionallysubstituted benzimidazolyl, an optionally substituted benzothiazolyl, anoptionally substituted benzothiadiazolyl, an optionally substitutedbenzoxadiazolyl, an optionally substituted indolyl, an optionallysubstituted tetrahydroindolyl, an optionally substituted azaindolyl, anoptionally substituted indazolyl, an optionally substitutedimidazopyridyl, an optionally substituted quinazolinyl, an optionallysubstituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidinyl,an optionally substituted pyrazolo[3,4]pyrimidinyl, or an optionallysubstituted benzo[b]thienyl; or R₃ is an optionally substitutedheterocycloalkyl; in certain preferred embodiments, R₃ is an optionallysubstituted piperidinyl, an optionally substituted piperazinyl, anoptionally substituted 2-oxopiperazinyl, an optionally substituted2-oxopiperidinyl, an optionally substituted 2-oxopyrrolidinyl, anoptionally substituted 4-piperidonyl, an optionally substitutedtetrahydropyranyl, an optionally substituted oxazolidinyl, an optionallysubstituted 2-oxo-oxazolidinyl, an optionally substitutedtetrahydrothiopyranyl, an optionally substituted tetrahydrothiopyranylsulfone, an optionally substituted morpholinyl, an optionallysubstituted thiomorpholinyl, an optionally substituted thiomorpholinylsulfoxide, an optionally substituted thiomorpholinyl sulfone, anoptionally substituted 1,3-dioxolanyl, an optionally substituted[1,4]dioxanyl, an optionally substituted 2-oxo-imidazolidinyl,tetrahydrofuranyl, or an optionally substituted tetrahydrothienyl; or R₃is cyano, halo, nitro, —OR^(k), —SR^(k), C(O)OR^(k), NR^(h)R^(j),C(O)NR^(h)R^(j), —OC(O)R^(k), —NR^(k)C(O)R^(k), —C(S)OR^(k), OC(S)R^(k),—NR^(k)C(O)NR^(h)R^(j), —NR^(k)C(S)NR^(h)R^(j), —C(O)NRhRj, —S(O)₂R^(k),—S(O)₂NR^(h)R^(j), —OC(O)NR^(h)R^(j), or —NR^(k)C(O)OR^(k), morepreferably R₃ is

in which each of A and A′, independently, is O, S, NH, or NR^(y),wherein R^(y) is a lower alkyl; each of R^(e) and R^(e′), independentlyis H, optionally substituted alkyl, optionally substituted aryl, oroptionally substituted heteroaryl; and m is 1 or 2; in certainembodiments, R₁ is

in which R^(t) is H, alkyl, or alkylcarbonyl; each R^(s) is,independently, chloro, cyano, methyl, ethyl, propyl, or phenyl; and r is1 or 2.

In certain preferred embodiments of formula (I), R₁ is

and each of R₂ and R₄ is H; R₃ is H, nitro, cyano, halo, —C(O)OR^(k),—OC(O)R^(k), —C(O)NR^(h)R^(j), —NR^(k)C(O)R^(k), —C(S)OR^(k),—OC(S)R^(k), —NR^(k)C(O)NR^(h)R^(j), —NR^(k)C(S)NR^(h)R^(j), —C(O)NRhRj,—S(O)₂R^(k), —S(O)₂NR^(h)R^(j), —OC(O)NR^(h)R^(j), —NR^(k)C(O)OR^(k), anoptionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cyclyl, optionallysubstituted heterocyclyl, optionally substituted alkyloxycarbonyl,optionally substituted alkylaminocarbonyl, or optionally substitutedalkylcarbonyl; G is absent; and X is NR^(k); in more preferredembodiments, X is NH; in other preferred embodiments, one of R^(a) andR^(b) is H or alkyl; and the other is aryl or heteroaryl wherein thearyl or the heteroaryl are optionally substituted with R^(q) and R_(z)^(r), in which R^(q) is halogen, CN, optionally substituted alkyl,optionally substituted alkyloxy, optionally substituted alkylcarbonyl,optionally substituted alkyloxycarbonyl, optionally substitutedaryloxycarbonyl, optionally substituted heteroaryloxycarbonyl,hydroxyalkyl, alkylamino, or alkylaminocarbonyl; R^(r) is halogen, CN,hydroxyl, optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted alkoxyl,optionally substituted aryloxyl, or optionally substitutedheteroaryloxyl; and z is 0, 1, 2, 3, or 4; still more preferably, one ofR^(a) and R^(b) is H or alkyl; and the other is

in which R^(q) is H, —OH, —NH₂, alkylamino, dialkylamino, alkyl,alkoxyl, methoxycarbonyl, or halo; each R^(r) is, independently, halo,CN, hydroxyl, —NH₂, alkylamino, dialkylamino, alkyl, aryl, heteroaryl,alkoxyl, aryloxyl, heteroaryloxyl, or —NHC(O)R^(y), wherein R^(y) is alower alkyl; and z is 0, 1, 2, 3, or 4. In certain embodiments, one ofQ, U and V is N, and the other two are each CH; more preferably, U is N,Q and V are each CH, Z is N, and W is O; or Q is N, U and V are each CH,Z is N, and W is O; or U is V, Q and U are each CH, Z is N, and W is O.In certain embodiments, R₃ is optionally substituted heteroaryl oroptionally substituted heterocyclyl; more preferably, R₃ is pyridinyl,1-oxy-pyridinyl, 1H-pyridin-2-one, morpholin-4-yl,4-methyl-piperazin-1-yl, or 2-oxo-oxazolidin-3-yl; still morepreferably, G is absent, n is 2, and Y is O; yet more preferably, X isNH; and still more preferably, one of R^(a) and R^(b) is H or alkyl, andthe other is

in which R^(q) is H, —OH, —NH₂, alkylamino, dialkylamino, alkyl,alkoxyl, methoxycarbonyl, or halogen; each R^(r) is, independently,halogen, CN, —OH, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(O)CH₃, lower alkoxy,alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, eteroaryloxyl, or—NHC(O)R^(y), wherein R^(y) is a lower alkyl; and z is 0, 1, 2, 3, or 4.In more preferred embodiments, one of R^(a) and R^(b) is H or methyl,and the other is

in which R^(r) is H, halo, CN, —OH, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(O)CH₃,lower alkoxy, or lower alkyl; more preferably, R^(r) is H, OH, NH₂, CNor F.

In still other embodiments of formula (I), Q, U and V is N, and theother two are each CH; more preferably Q is N and U and V are each CH;or V is N and Q and U are each CH; or U is N and Q and V are each CH.

In certain preferred embodiments of the compounds of formula (I), Y isO, n is 2, R₂ and R₄ are H for all occurrences, G is absent, and R₃ isR^(g), in which R^(g) is optionally substituted heterocyclyl, morepreferably morpholinyl, still more preferably morpholin-4-yl.

In another aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound offormula (I), supra. In preferred embodiments, R₁ is

each of R₂ and R₄ is H; R₃ is H, —C(O)OR^(k), —OC(O)R^(k),—C(O)NR^(h)R^(j), —NR^(k)C(O)R^(k), —C(S)OR^(k), —OC(S)R^(k),—NR^(k)C(O)NR^(h)R^(j), —NR^(k)C(S)NR^(h)R^(j), —C(O)NR^(h)R^(j),—S(O)₂R^(k), —S(O)₂NR^(h)R^(j), —OC(O)NR^(h)R^(j), or —NR^(k)C(O)OR^(k),a halo, nitro, cyano, an optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cyclyl, optionally substituted heterocyclyl, optionallysubstituted alkyloxycarbonyl, optionally substituted alkylaminocarbonyl,or optionally substituted alkylcarbonyl; and X is NR^(k). In certainpreferred pharmaceutical compositions, the compound is characterized inthat one of R^(a) and R^(b) is H or alkyl; and the other is aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substitutedwith R^(q) and R_(z) ^(r), in which R^(q) is halogen, CN, —NH₂,alkylamino, dialkylamino, alkyl, alkyloxy, alkylcarbonyl,alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl,alkylamino, or alkylaminocarbonyl; each R^(r) is, independently,halogen, CN, hydroxyl, —NH₂, alkylamino, dialkylamino, alkyl, aryl,heteroaryl, alkoxyl, aryloxyl, heteroaryloxyl or —NHC(O)R^(y), whereinR^(y) is a lower alkyl; and z is 0, 1, 2, 3, or 4.

In more preferred embodiments, compounds of the invention include thefollowing:

Compound 1:N-{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-4-yl}-N′-(1H-indol-3-ylmethylene)-hydrazine;

Compound 2:N-{6-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(1H-indol-3-ylmethylene)-hydrazine;

Compound 3:N-{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-N′-(1H-indol-3-ylmethylene)-hydrazine;

Compound 4:{6-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-(2,3-dimethyl-1H-indol-5-yl)-amine;

Compound 5:N-{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine;

Compound 6:N-{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-4-yl}-N′-(3-methyl-benzylidene)-hydrazine;

Compound 7:N-{6-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine;

Compound 8:{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-4-yl}-(2,3-dimethyl-1H-indol-5-yl)-amine;

Compound 9:{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-(2,3-dimethyl-1H-indol-5-yl)-amine;

Compound 10:{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-m-tolyl-amine.

Their structures are delineated below.

Additional compounds of the invention include the following:

N-(3-Ethyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methoxy-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

Methyl-(3-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenyl)-amine

N-(3-Methyl-benzylidene)-N′-{4-morpholin-4-yl-6-[2-(4-oxy-morpholin-4-yl)-ethoxy]-pyridin-2-yl}-hydrazine

Dimethyl-(3-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenyl)-amine

N-(3-Cyclopropyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Fluoro-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Chloro-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Bromo-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Iodo-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3,4-Dimethyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(2,5-Dimethyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

4-Methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenol

4-Methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenylamine

Methyl-(4-methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenyl)-amine

Dimethyl-(4-methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenyl)-amine

N-Methyl-N-(4-methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenyl)-acetamide

N-Ethyl-N′-(3-methyl-benzylidene)-N-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

3-Methyl-benzaldehydeO-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-oxime

3-Methyl-benzaldehydeO-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-thiooxime

N-Methyl-N-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-(1-m-tolyl-ethylidene)-hydrazine

N-[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-(1-m-tolyl-propylidene)-hydrazine

3-{[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzoicacid methylester

3-{[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzoicacid ethyl ester

3-{[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzoicacid isopropylester

3-{[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzoicacid

3-{[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzamide

N-Methyl-3-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzamide

N-Cyclopropyl-3-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzamide

3-Methyl-5-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzamide

3-Hydroxymethyl-5-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-benzamide

N-(3-Methyl-benzylidene)-N′-[5-methyl-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-[5-Fluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-[5-Chloro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-Benzylidene-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-{6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-piperazin-1-yl-ethoxy)-pyridin-2-yl]-hydrazine

Acetic acidN-{6-[2-(4-acetyl-piperazin-1-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazide

1-[4-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-piperazin-1-yl]-ethanone

N-{6-[2-(4-Ethyl-piperazin-1-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-{6-[2-(4-Ethyl-3-methyl-piperazin-1-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-{6-[2-(4-Ethyl-2-methyl-piperazin-1-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-{6-[2-(2,6-Dimethyl-morpholin-4-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(3-morpholin-4-yl-propyl)-pyridin-2-yl]-hydrazine

1-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-3-morpholin-4-yl-propan-1-one

{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-(2-morpholin-4-yl-ethyl)-amine

Methyl-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-(2-morpholin-4-yl-ethyl)-amine

Ethyl-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-(2-morpholin-4-yl-ethyl)-amine

N-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-N-(2-morpholin-4-yl-ethyl)-acetamide

N-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-2-morpholin-4-yl-acetamide

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethylsulfanyl)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-piperidin-1-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-2-yl]-hydrazine

1-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-pyrrolidin-2-one

1-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-pyrrolidine-2,5-dione

Ethyl-methyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

Diethyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

Ethyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

Methyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethylamine

Cyclohexyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

N-(3-Methyl-benzylidene)-N′-{4-morpholin-4-yl-6-[2-(octahydro-indol-1-yl)-ethoxy]-pyridin-2-yl}-hydrazine

Cyclohex-1-enyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

Cyclopent-3-enyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-(tetrahydro-pyran-4-yl)-amine

Cyclohexylidene-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-amine

(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-carbamicacid methyl ester

(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-carbamicacid ethyl ester

(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-carbamicacid isopropyl ester

1-Isopropyl-3-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-urea

1-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-3-phenyl-urea

1-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-3-pyridin-3-yl-urea

(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-carbamicacid pyridin-3-ylester

N-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-N′-propyl-guanidine

N-Methyl-N′-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-N″-propyl-guanidine

N-Cyano-N′-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-N″-propyl-guanidine

N-Nitro-N′-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-N″-propyl-guanidine

Propyl-carbamic acid2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl-ester

Phenyl-carbamic acid2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethylester

Dimethyl-carbamic acid2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethylester

1-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-imidazolidine-2-thione

1-Methyl-3-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-imidazolidine-2-thione

1-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-pyrrolidin-2-one

N-[6-(2-[1,3]Dioxolan-2-yl-ethoxy)-4-morpholin-4-yl-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

Piperidine-1-carboxylic acid2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethylester

Morpholine-4-carboxylic acid2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethylester

Cyclohexanecarboxylic acid2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethylester

Cyclohexanecarboxylic acid3-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-propylester

3-Hydroxy-propionic acid3-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-propylester

3-Dimethylamino-propionic acid3-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-propylester

Dimethylamino-acetic acid3-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-propylester

Piperidin-1-yl-acetic acid3-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-propylester

5-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-1-piperidin-1-yl-pentan-2-one

N-Cyclohexyl-4-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-butyramide

4-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-butyricacid cyclohexyl ester

4-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-butyricacid sec-butyl ester

N-sec-Butyl-4-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-butyramide

N-(2-Hydroxy-ethyl)-4-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-butyramide

4-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-butyronitrile

N-(6-Hex-4-ynyloxy-4-morpholin-4-yl-pyridin-2-yl)-N′-(3-methyl-benzylidene)-hydrazine

4-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethoxy)-butan-1-ol

2-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethoxy)-ethanol

N-{6-[2-(2-Methoxy-ethoxy)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-[6-(2-Ethoxy-ethoxy)-4-morpholin-4-yl-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(3-phenyl-propyl)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-pyrazin-2-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-thiophen-2-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-thiazol-5-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-thiazol-2-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(3-Methyl-benzylidene)-N′-{6-[2-(2-methyl-thiazol-5-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-hydrazine

N-(3-Methyl-benzylidene)-N′-{6-[2-(2-methyl-oxazol-5-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-hydrazine

N-(3-Methyl-benzylidene)-N′-{6-[2-(2-methyl-3H-imidazol-4-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-hydrazine

N-{6-[2-(2,3-Dimethyl-3H-imidazol-4-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-[6-(2-Imidazo[1,2-a]pyridin-3-yl-ethoxy)-4-morpholin-4-yl-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-{6-[2-(1H-Indol-3-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

1-[3-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-indol-1-yl]-ethanone

1-[3-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-pyrrolo[3,2-c]pyridin-1-yl]-ethanone

N-(3-Methyl-benzylidene)-N′-[6-(3-methyl-pent-3-enyloxy)-4-morpholin-4-yl-pyridin-2-yl]-hydrazine

N-(6-Ethoxy-4-morpholin-4-yl-pyridin-2-yl)-N′-(3-methyl-benzylidene)-hydrazine

N-(6-Isopropoxy-4-morpholin-4-yl-pyridin-2-yl)-N′-(3-methyl-benzylidene)-hydrazine

N-(3-Methyl-benzylidene)-N′-(4-morpholin-4-yl-6-propoxy-pyridin-2-yl)-hydrazine

N-(6-Heptyloxy-4-morpholin-4-yl-pyridin-2-yl)-N′-(3-methyl-benzylidene)-hydrazine

4-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethoxy)-butan-2-one

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-phenoxy-ethoxy)-pyridin-2-yl]-hydrazine

N-{6-[2-(4-Fluoro-phenoxy)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

N-(3-Methyl-benzylidene)-N′-{4-morpholin-4-yl-6-[2-(pyridin-2-yloxy)-ethoxy]-pyridin-2-yl}-hydrazine

N-{6-[2-(5-Fluoro-pyridin-2-yloxy)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

6-(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethoxy)-pyridin-3-ol

4-(3-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-propyl)-benzoicacidmethyl ester

N-{6-[2-(5-Chloro-pyridin-2-yloxy)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine

(2-{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-pyridin-2-yl-amine

Methyl-(2-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-pyridin-2-yl-amine

N-(3-Methyl-benzylidene)-N′-{4-morpholin-4-yl-6-[3-(1-oxy-pyridin-2-yl)-propoxy]-pyridin-2-yl}-hydrazine

N-(3-Methyl-benzylidene)-N′-{4-morpholin-4-yl-6-[2-(1-oxy-pyridin-2-yloxy)-ethoxy]-pyridin-2-yl}-hydrazine

6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridine-2-carboxylicacid methyl ester

6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridine-2-carboxylicacid dimethylamide

{6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-piperidin-1-yl-methanone

N-(3-Methyl-benzylidene)-N′-(4-morpholin-4-yl-6-phenoxy-pyridin-2-yl)-hydrazine

N-[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-naphthalen-2-ylmethylene-hydrazine

N-Benzofuran-5-ylmethylene-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-Benzo[b]thiophen-5-ylmethylene-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(4,5-Dimethyl-pyridin-2-ylmethylene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-[1-(4-Methyl-pyridin-2-yl)-ethylidene]-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

1H-Indole-3-carbaldehydeO-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-oxime

1-(3-{[4-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-indol-1-yl)-ethanone

N-(1-Methanesulfonyl-1H-indol-3-ylmethylene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-(1H-Indazol-3-ylmethylene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-Benzo[d]isoxazol-3-ylmethylene-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-Benzo[d]isoxazol-3-ylmethylene-N′-[6-morpholin-4-yl-4-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

N-Benzo[d]isoxazol-3-ylmethylene-N′-[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazine

N-Benzo[d]isothiazol-3-ylmethylene-N′-[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazine

N-(1H-Indazol-3-ylmethylene)-N′-[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazine

N-(1H-Indol-3-ylmethylene)-N′-[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazine

N-Benzofuran-3-ylmethylene-N′-[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazine

N-(6-Methyl-1H-indol-3-ylmethylene)-N′-[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazine

Dimethyl-(3-{[2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazonomethyl}-1H-indol-6-yl)-amine

3-{[2-Morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-hydrazonomethyl}-1H-indole-6-carboxylicacidmethylamide

N-(4,6-Di-morpholin-4-yl-pyridin-2-yl)-N′-(3-methyl-benzylidene)-hydrazine

N-(3-Methyl-benzylidene)-N′-(4′-morpholin-4-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-hydrazine

N-(3-Methyl-benzylidene)-N′-(4-morpholin-4-yl-6-thiomorpholin-4-yl-pyridin-2-yl)-hydrazine

Ethyl-methyl-{6-[N′-(3-methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridin-2-yl}-amine

6-[N′-(3-Methyl-benzylidene)-hydrazino]-4-morpholin-4-yl-pyridine-2-carboxylicacid 2-morpholin-4-yl-ethylester

N-(3-Methyl-benzylidene)-N′-{4-morpholin-4-yl-6-[2-(pyridin-2-yloxy)-ethoxy]-pyridin-2-yl}-hydrazine

(9H-Carbazol-3-yl)-[6-morpholin-4-yl-4-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-amine

Dibenzofuran-2-yl-[6-morpholin-4-yl-4-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-amine

3-[6-Morpholin-4-yl-4-(2-morpholin-4-yl-ethoxy)-pyridin-2-yloxy]-9H-carbazole

(2,3-Dimethyl-1H-indol-5-yl)-[6-morpholin-4-yl-4-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-amine

[4-(2-Diethylamino-ethoxy)-6-morpholin-4-yl-pyridin-2-yl]-(2,3-dimethyl-1H-indol-5-yl)-amine

N-{2-[2-(2,3-Dimethyl-1H-indol-5-ylamino)-6-morpholin-4-yl-pyridin-4-yloxy]-ethyl}-N-ethyl-acetamide

(2,3-Dimethyl-1H-indol-5-yl)-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-amine

4-{2-[2-(2,3-Dimethyl-1H-indol-5-ylamino)-6-morpholin-4-yl-pyridin-4-yloxy]-ethyl}-1-methyl-piperidin-2-one

(2,3-Dichloro-1H-indol-5-yl)-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-amine

{4-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

[6-Morpholin-4-yl-4-(2-pyridin-2-yl-ethoxy)-pyridin-2-yl]-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

[2-Morpholin-4-yl-6-(2-pyridin-2-yl-ethoxy)-pyridin-4-yl]-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

[4-Morpholin-4-yl-6-(2-pyridin-2-yl-ethoxy)-pyridin-2-yl]-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

[4-Morpholin-4-yl-6-(2-pyrazin-2-yl-ethoxy)-pyridin-2-yl]-(6,7,8,9-tetrahydro-5H-carbazol-3-yl)-amine

Still more compounds of the invention are the following:

N-[3,5-Difluoro-6-morpholin-4-yl-4-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-[3,5-Difluoro-6-morpholin-4-yl-4-(2-pyridin-2-yl-ethoxy)-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-[3,5-Difluoro-4-morpholin-4-yl-6-(2-pyridin-2-yl-ethoxy)-pyridin-2-yl]-N′-naphthalen-2-ylmethylene-hydrazine

1-[3,5-Difluoro-4-morpholin-4-yl-6-(N′-naphthalen-2-ylmethylene-hydrazino)-pyridin-2-yloxy]-2-methyl-propan-2-ol

3-{2-[3,5-Difluoro-6-morpholin-4-yl-4-(N′-naphthalen-2-ylmethylene-hydrazino)-pyridin-2-yloxy]-ethyl}-oxazolidin-2-one

3-(2-{4-[N′-(3,4-Dimethyl-benzylidene)-hydrazino]-3,5-difluoro-6-morpholin-4-yl-pyridin-2-yloxy}-ethyl)-oxazolidin-2-one

4-{4-[N′-(3,4-Dimethyl-benzylidene)-hydrazino]-3,5-difluoro-6-morpholin-4-yl-pyridin-2-yl}-2-methyl-butan-2-ol

2-{3,5-Difluoro-4-[N′-(1H-indol-3-ylmethylene)-hydrazino]-6-morpholin-4-yl-pyridin-2-yloxy}-ethanol

N-[3,5-Difluoro-4-(2-methoxy-ethoxy)-6-morpholin-4-yl-pyridin-2-yl]-N′-(1H-indol-3-ylmethylene)-hydrazine

N-{3,5-Difluoro-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(6-methyl-1H-indol-3-ylmethylene)-hydrazine

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-1-oxy-pyridin-2-yl]-hydrazine

In another aspect, the invention provides a pharmaceutical composition.The pharmaceutical composition includes a pharmaceutically acceptablecarrier and a compound of the invention, e.g., any of the formulae ornamed compounds described herein. Thus, in one embodiment, thepharmaceutical composition comprises a compound of any of the formulaeherein or a pharmaceutically acceptable salt, solvate, clathrate,hydrate, polymorph, or prodrug thereof, and a pharmaceuticallyacceptable carrier.

The compounds of the invention are particularly useful in inhibiting theproduction of IL-12 and/or inhibiting the production of cytokines suchas IL-23 and IL-27 which stimulate and/or otherwise augment theproduction of IL-12 and/or the proliferation of T_(H)1 lymphocytes.Thus, in one aspect, the present invention provides a method ofinhibiting the production of IL-12 and/or inhibiting the production of acytokine that stimulates or facilitates the production of IL-12 (e.g.,IL-23 and IL-27) in a subject by administering to the subject aneffective amount of a compound of any of the formulae herein, or apharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph, or prodrug thereof.

In another aspect, the invention provides a method of inhibiting IL-23production in a subject, comprising administering to the subject aneffective amount of a compound of the invention, e.g., any of theformulae or named compounds described herein, or pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugthereof. In preferred embodiments, the method further comprisesinhibiting the production of IL-12.

In another aspect, the invention provides a method of inhibiting IL-27production in a subject, comprising administering to the subject aneffective amount of a compound of the invention, e.g., any of theformulae or named compounds described herein, or pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, polymorph, or prodrugthereof. In preferred embodiments, the method further comprisesinhibiting T_(H)1 lymphocyte proliferation; more preferably, the methodstill further comprises inhibiting the production of IL-12.

In another aspect, the invention provides method for treating aninterleukin-12 production-related disorder, comprising administering toa subject in need thereof an effective amount of a compound of any ofthe formulae herein, or a pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph, or prodrug thereof. In certainembodiments, the disorder is selected from the group consisting ofmultiple sclerosis, sepsis, myasthenia gravis, autoimmune neuropathies,Guillain-Barré syndrome, autoimmune uveitis, autoimmune hemolyticanemia, pernicious anemia, autoimmune thrombocytopenia, temporalarteritis, anti-phospholipid syndrome, vasculitides, Wegener'sgranulomatosis, Behcet's disease, psoriasis, psoriatic arthritis,dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease,ulcerative colitis, interstitial pulmonary fibrosis, myelofibrosis,hepatic fibrosis, myocarditis, thyroditis, primary biliary cirrhosis,autoimmune hepatitis, immune-mediated diabetes mellitus, Grave'sdisease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland; rheumatoid arthritis, juvenilerheumatoid arthritis, systemic lupus erythematosus, scleroderma,polymyositis, dermatomyositis, spondyloarthropathies, ankylosingspondylitis, Sjogren's syndrome and graft-versus-host disease, morepreferably rheumatoid arthritis, sepsis, Crohn's disease, multiplesclerosis, psoriasis, or immune-mediated diabetes mellitus. In certainpreferred embodiments, in the compound of formula (I), R₁ is;

each of R₂ and R₄ is H; R₃ is H, —C(O)OR^(k), —OC(O)R^(k),—C(O)NR^(h)R^(j), —NR^(k)C(O)R^(k), —C(S)OR^(k), —OC(S)R^(k),—NR^(k)C(O)NR^(h)R^(j), —NR^(k)C(S)NR^(h)R^(j), —C(O)NRhRj, —S(O)₂R^(k),—S(O)₂NR^(h)R^(j), —OC(O)NR^(h)R^(j), or —NR^(k)C(O)OR^(k), a halo,nitro, cyano, an optionally substituted alkyl, an optionally substitutedaryl, an optionally substituted heteroaryl, an optionally substitutedcyclyl, an optionally substituted heterocyclyl, an optionallysubstituted alkyloxycarbonyl, an optionally substitutedalkylaminocarbonyl, or an optionally substituted alkylcarbonyl; and X isNR^(k); more preferably, one of R^(a) and R^(b) is H or alkyl, and theother is aryl or heteroaryl, wherein the aryl or heteroaryl isoptionally substituted with R^(q) and R_(z) ^(r), and wherein R^(q) ishalogen, CN, —NH₂, alkylamino, dialkylamino, alkyl, alkyloxy,alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,hydroxyalkyl, alkylamino, or alkylaminocarbonyl; each R^(r) is,independently, halogen, CN, —NH₂, alkylamino, dialkylamino, hydroxyl,alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, heteroaryloxyl, or—NHC(O)R^(y), wherein R^(y) is a lower alkyl; and z is 0, 1, 2, 3, or 4.

In another aspect, the invention provides a method for treating orpreventing disorders associated with excessive bone loss, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of any of the formulae herein, or apharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph, or prodrug thereof. In preferred embodiments, the disorder isperiodontal disease, non-malignant bone disorders, osteoporosis, Paget'sdisease of bone, osteogenesis imperfecta, fibrous dysplasia, and primaryhyperparathyroidism, estrogen deficiency, inflammatory bone loss, bonemalignancy, arthritis, osteopetrosis, hypercalcemia of malignancy (HCM),osteolytic bone lesions of multiple myeloma and osteolytic bonemetastases of breast cancer, and metastatic cancers.

In another aspect, the invention provides a method for inhibitingosteoclast formation in vitro or in vivo, the method comprisingcontacting a pre-osteoclast cell with an effective amount of a compoundof any of the formulae herein, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate, polymorph, or prodrug thereof.

In another aspect, the invention provides a method of treating orpreventing a disorder associated with excessive bone resorption byosteoclasts in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compound of any ofthe formulae herein, or a pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph, or prodrug thereof.

Since the function of IL-12 is induction of INF-γ expression from T andNK cells which promotes the development of T_(H)1 T lymphocyte type, thecompounds of the invention can be used to inhibit the production ofT_(H)1 cells. Therefore, in another aspect, the invention features amethod of inhibiting the production and/or development of T_(H)1 cellsin a subject by administering to the subject an effective amount of acompound of any of the formulae herein, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymorph, or prodrug thereof.

In still another embodiment, the invention provides a method ofinhibiting the proliferation of T_(H)1 lymphocytes in a subject,comprising administering to the subject an effective amount of acompound of the invention, e.g., a compound of formula (I) or anycompound named herein.

In another aspect, the invention provides a method of treating an IL-12overproduction-related disorder, comprising administering to a subjectin need thereof a therapeutically effective amount of a compound of anyof the formulae herein or a pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph, or prodrug thereof. IL-12 overproductiondisorders include, but are not limited to multiple sclerosis, sepsis,myasthenia gravis, autoimmune neuropathies, Guillain-Barré syndrome,autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia,autoimmune thrombocytopenia, temporal arteritis, anti-phospholipidsyndrome, vasculitides, Wegener's granulomatosis, Behcet's disease,psoriasis, psoriatic arthritis, dermatitis herpetiformis, pemphigusvulgaris, vitiligo, Crohn's disease, ulcerative colitis, interstitialpulmonary fibrosis, myelofibrosis, hepatic fibrosis, myocarditis,thyroditis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 orimmune-mediated diabetes mellitus, Grave's disease, Hashimoto'sthyroiditis, autoimmune oophoritis and orchitis, autoimmune disease ofthe adrenal gland; rheumatoid arthritis, juvenile rheumatoid arthritis,systemic lupus erythematosus, scleroderma, polymyositis,dermatomyositis, spondyloarthropathies, ankylosing spondylitis,Sjogren's syndrome and graft-versus-host disease.

In another aspect, the invention provides a method of inhibiting theproduction of IL-12 and/or inhibiting the production of a cytokine thatstimulates or facilitates the production of IL-12 (e.g., IL-23 andIL-27) in a subject. The method includes administering to the subject acompound of any of the formulae herein or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymorph, or prodrug thereof.

Although the mechanism is not yet understood, compounds of the inventionhave been found to inhibit the formation of osteoclasts (see co-ownedPCT Application Number US04/17064 filed on May 28, 2004, the entireteachings of which are incorporated herein by reference). Osteoclastsare unique multinucleated cells within bone that are responsible forbone degradation and resorption. These are the only cells in the bodyknown to be capable of this function. The regulation of osteoclasticformation and activity is only partly understood but it is known thatexcessive bone resorption by osteoclasts contributes to the pathology ofmany human diseases associated with excessive bone loss. Thus, in oneaspect, the invention provides a method of treating or preventingdisorders associated with excessive bone loss, comprising administeringto a subject in need thereof a therapeutically effective amount of acompound of any of the formulae herein or pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymorph, or prodrug thereof.Disorders associated with excessive bone loss include, but are notlimited to periodontal disease, non-malignant bone disorders,osteoporosis, Paget's disease of bone, osteogenesis imperfecta, fibrousdysplasia, and primary hyperparathyroidism, estrogen deficiency,inflammatory bone loss, bone malignancy, arthritis, osteopetrosis,hypercalcemia of malignancy (HCM), osteolytic bone lesions of multiplemyeloma and osteolytic bone metastases of breast cancer, and metastaticcancers.

In another aspect, the invention provides a method for inhibitingosteoclast formation in vitro or in vivo, comprising contacting apre-osteoclast cell with an effective amount of a compound of any of theformulae herein or pharmaceutically acceptable salt, solvate, clathrate,hydrate, polymorph, or prodrug thereof.

In another aspect, the invention provides a method of treating orpreventing a disorder associated with excessive bone resorption byosteoclasts in a subject in need thereof, comprising administering tothe subject an effective amount of a compound of any of the formulaeherein or pharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph, or prodrug thereof. The method includes administering to thesubject (including a subject identified as in need of such treatment) aneffective amount of a compound described herein, or a compositiondescribed herein to produce such effect. Identifying a subject in needof such treatment can be in the judgment of a subject or a health careprofessional and can be subjective (e.g. opinion) or objective (e.g.measurable by a test or diagnostic method).

In another aspect, the invention provides a method of treating orpreventing an inflammatory disorder in a subject in need thereof, themethod comprising administering to the subject an effective amount of acompound of the invention, e.g., any of the formulae or named compoundsdescribed herein, or pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph, or prodrug thereof. In certainembodiments, the inflammatory disorder is asthma, adult respiratorydistress syndrome, systemic lupus erythematosus, inflammatory boweldisease (including Crohn's disease and ulcerative colitis), multiplesclerosis, insulin-dependent diabetes mellitus, autoimmune arthritis(including rheumatoid arthritis, juvenile rheumatoid arthritis,psoriatic arthritis), inflammatory pulmonary syndrome, pemphigusvulgaris, idiopathic thrombocytopenic purpura, autoimmune meningitis,myasthenia gravis, autoimmune thyroiditis, dermatitis (including atopicdermatitis and eczematous dermatitis), psoriasis, Sjogren's Syndrome(including keratoconjunctivitis sicca secondary to Sjogren's Syndrome),alopecia areata, allergic responses due to arthropod bite reactions,aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, cutaneouslupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions(such as Stevens-Johnson syndrome), leprosy reversal reactions, erythemanodosum leprosum, autoimmune uveitis, allergic encephalomyelitis,aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia,polychondritis, Wegener's granulomatosis, chronic active hepatitis,Graves opthalmopathy, primary biliary cirrhosis, uveitis posterior, orinterstitial lung fibrosis.

In another aspect, the invention provides a method of treating orpreventing an immune disease in a subject in need thereof, the methodcomprising administering to the subject an effective amount of acompound of the invention, e.g., any of the formulae or named compoundsdescribed herein, or pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph, or prodrug thereof. In certainembodiments, the immune disease is rheumatoid arthritis, juvenilerheumatoid arthritis, systemic onset juvenile rheumatoid arthritis,psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegativearthropathies, osteoarthritis, inflammatory bowel disease, ulcerativecolitis, systemic lupus erythematosis, antiphospholipid syndrome,iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis,systemic vasculitis/wegener's granulomatosis, sarcoidosis,orchitis/vasectomy reversal procedures, allergic/atopic diseases,asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergicconjunctivitis, hypersensitivity pneumonitis, transplants, organtransplant rejection, graft-versus-host disease, systemic inflammatoryresponse syndrome, sepsis syndrome, gram positive sepsis, gram negativesepsis, culture negative sepsis, fungal sepsis, neutropenic fever,urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiationexposure, acute pancreatitis, adult respiratory distress syndrome,rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatorypathologies, sarcoidosis, Crohn's pathology, sickle cell anemia,diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergicrhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis,asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia,hemolytic disesease, thrombocytopenia, graft rejection of any organ ortissue, kidney translplant rejection, heart transplant rejection, livertransplant rejection, pancreas transplant rejection, lung transplantrejection, bone marrow transplant (BMT) rejection, skin allograftrejection, cartilage transplant rejection, bone graft rejection, smallbowel transplant rejection, fetal thymus implant rejection, parathyroidtransplant rejection, xenograft rejection of any organ or tissue,allograft rejection, anti-receptor hypersensitivity reactions, Gravesdisease, Raynoud's disease, type B insulin-resistant diabetes, asthma,myasthenia gravis, antibody-meditated cytotoxicity, type IIIhypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), polyneuropathy, organomegaly,endocrinopathy, monoclonal gammopathy, skin changes syndrome,antiphospholipid syndrome, pemphigus, scleroderma, mixed connectivetissue disease, idiopathic Addison's disease, diabetes mellitus, chronicactive hepatitis, primary billiary cirrhosis, vitiligo, vasculitis,post-MI cardiotomy syndrome, type IV hypersensitivity, contactdermatitis, hypersensitivity pneumonitis, allograft rejection,granulomas due to intracellular organisms, drug sensitivity,metabolic/idiopathic, Wilson's disease, hemachromatosis,alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto'sthyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axisevaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis,cachexia, cystic fibrosis, neonatal chronic lung disease, chronicobstructive pulmonary disease (COPD), familial hematophagocyticlymphohistiocytosis, dermatologic conditions, psoriasis, alopecia,nephrotic syndrome, nephritis, glomerular nephritis, acute renalfailure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy,anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy(e.g., including but not limited toasthenia, anemia, cachexia, and thelike), or chronic salicylate intoxication.

In another aspect, the invention provides a method of treating orpreventing a neurological disorder in a subject in need thereof, themethod comprising administering to the subject an effective amount of acompound of the invention, e.g., any of the formulae or named compoundsdescribed herein, or pharmaceutically acceptable salt, solvate,clathrate, hydrate, polymorph, or prodrug thereof. In certainembodiments, the neurological disorder is a neurodegenerative disease,multiple sclerosis, migraine headache, AIDS dementia complex,demyelinating disease, such as multiple sclerosis and acute transversemyelitis; extrapyramidal and cerebellar disorders such as lesions of thecorticospinal system; disorders of the basal ganglia or cerebellardisorders; hyperkinetic movement disorders such as Huntington's Choreaand senile chorea; drug-induced movement disorders, such as thoseinduced by drugs which block CNS dopamine receptors; hypokineticmovement disorders, such as Parkinson's disease; Progressive supranucleoPalsy; structural lesions of the cerebellum; spinocerebellardegenerations, such as spinal ataxia, Friedreich's ataxia, cerebellarcortical degenerations, multiple systems degenerations (Mencel,Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders(Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, andmitochondrial multi.system disorder); demyelinating core disorders, suchas multiple sclerosis, acute transverse myelitis; and disorders of themotor unit such as neurogenic muscular atrophies (anterior horn celldegeneration, such as amyotrophic lateral sclerosis, infantile spinalmuscular atrophy and juvenile spinal muscular atrophy); Alzheimer'sdisease; Down's Syndrome in middle age; Diffuse Lewy body disease;Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronicalcoholism; Creutzfeldt-Jakob disease; Subacute sclerosingpanencephalitis, Hallerrorden-Spatz disease; or Dementia pugilistica.

Other embodiments include the compounds, intermediates, or apharmaceutically acceptable salt, solvate, clatharate, hydrate,polymorph, or prodrug thereof delineated herein, or compositionsincluding them; as well as their methods of use for treatment orprevention of disease, inhibition of IL-12, or modulation of IL-12mediated disease.

Another embodiment is a method of making a compound of any of theformulae herein using any one, or combination of, reactions delineatedherein. The method can include the use of one or more intermediates orchemical reagents delineated herein.

Another aspect is a radiolabeled compound of any of the formulaedelineated herein. Such compounds have one or more radioactive atoms(e.g., ³H, ²H, ¹⁴C, ¹³C, ³²P, ³⁵S, ¹²⁵I, ¹³¹I) introduced into thecompound. Such compounds are useful for drug metabolism studies anddiagnostics.

As used herein, the term “alkyl” refers to a straight-chained orbranched hydrocarbon group containing 1 to 12 carbon atoms. The term“lower alkyl” refers to a C₁-C₆ alkyl chain. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, tert-butyl, and n-pentyl.Alkyl groups may be optionally substituted with one or moresubstituents.

The term “alkenyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing 2 to 12 carbon atomsand at least one carbon-carbon double bond. Alkenyl groups may beoptionally substituted with one or more substituents.

The term “alkynyl” refers to an unsaturated hydrocarbon chain that maybe a straight chain or branched chain, containing the 2 to 12 carbonatoms and at least one carbon-carbon triple bond. Alkynyl groups may beoptionally substituted with one or more substituents.

The sp² or sp carbons of an alkenyl group and an alkynyl group,respectively, may optionally be the point of attachment of the alkenylor alkynyl groups.

The term “alkoxy” refers to an —O-alkyl radical. The term “ester” refersto a —C(O)O—R^(k); or, where a divalent group is indicated, an “ester”group is —C(O)O— or —OC(O)—. An “amido” is an —C(O)NH₂, and an“N-alkyl-substituted amido” is of the formula C(O)NHR^(k); where adivalent “amide” group is indicated, the group is —C(O)N^(k)— or—N^(k)C(O)—.

The term “mercapto” refers to a —SH group.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

As used herein, the term “haloalkyl” means and alkyl group in which oneor more (including all) the hydrogen radicals are replaced by a halogroup, wherein each halo group is independently selected from —F, —Cl,—Br, and —I. The term “halomethyl” means a methyl in which one to threehydrogen radical(s) have been replaced by a halo group. Representativehaloalkyl groups include trifluoromethyl, bromomethyl,1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

The term “cycloalkyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one non-aromatic,completely saturated ring. Cycloalkyl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a cycloalkyl group may be substituted by asubstituent. Representative examples of cycloalkyl group includecyclopropyl, cyclopentyl, cyclohexyl, cyclobutyl, cycloheptyl,cyclooctyl, cyclononyl, and cyclodecyl.

The term “cyclyl” refers to a hydrocarbon 3-8 membered monocyclic or7-14 membered bicyclic ring system having at least one non-aromaticring, wherein the non-aromatic ring has some degree of unsaturation.Cyclyl groups may be optionally substituted with one or moresubstituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of each ring ofa cyclyl group may be substituted by a substituent. Examples of cyclylgroups include cyclohexenyl, bicyclo[2.2.1]hept-2-enyl,dihydronaphthalenyl, benzocyclopentyl, cyclopentenyl, cyclopentadienyl,cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl,cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl,cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl,cyclodecadienyl and the like.

The term “aryl” refers to a hydrocarbon monocyclic, bicyclic ortricyclic aromatic ring system. Aryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, 4, 5 or 6 atoms of each ring of an aryl group may be substituted by asubstituent. Examples of aryl groups include phenyl, naphthyl,anthracenyl, fluorenyl, indenyl, azulenyl, and the like.

As used herein, the term “aralkyl” means an aryl group that is attachedto another group by a (C₁-C₆)alkylene group. Aralkyl groups may beoptionally substituted, either on the aryl portion of the aralkyl groupor on the alkylene portion of the aralkyl group, with one or moresubstituent. Representative aralkyl groups include benzyl,2-phenyl-ethyl, naphth-3-yl-methyl and the like.

As used herein, the term “alkylene” refers to an alkyl group that hastwo points of attachment. The term “(C₁-C₆)alkylene” refers to analkylene group that has from one to six carbon atoms. Non-limitingexamples of alkylene groups include methylene (—CH₂—), ethylene(—CH₂CH₂—), n-propylene (—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), andthe like.

The term “arylalkoxy” refers to an alkoxy substituted with aryl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-4 ring heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andthe remainder ring atoms being carbon (with appropriate hydrogen atomsunless otherwise indicated). Heteroaryl groups may be optionallysubstituted with one or more substituents. In one embodiment, 0, 1, 2,3, or 4 atoms of each ring of a heteroaryl group may be substituted by asubstituent. Examples of heteroaryl groups include pyridyl,1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl,pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl thiazolyl, isoxazolyl,quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl,benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, andbenzo[b]thienyl, 3H-thiazolo[2,3-c][1,2,4]thiadiazolyl,imidazo[1,2-d]-1,2,4-thiadiazolyl, imidazo[2,1-b]-1,3,4-thiadiazolyl,1H,2H-furo[3,4-d]-1,2,3-thiadiazolyl,1H-pyrazolo[5,1-c]-1,2,4-triazolyl, pyrrolo[3,4-d]-1,2,3-triazolyl,cyclopentatriazolyl, 3H-pyrrolo[3,4-c]isoxazolyl,1H,3H-pyrrolo[1,2-c]oxazolyl, pyrrolo[2,1b]oxazolyl, and the like.

As used herein, the term “heteroaralkyl” or “heteroarylalkyl” means aheteroaryl group that is attached to another group by a (C₁-C₆)alkylene.Heteroaralkyl groups may be optionally substituted, either on theheteroaryl portion of the heteroaralkyl group or on the alkylene portionof the heteroaralkyl group, with one or more substituent. Representativeheteroaralkyl groups include 2-(pyridin-4-yl)-propyl,2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like.

The term “heterocycloalkyl” refers to a nonaromatic, completelysaturated 3-8 membered monocyclic, 7-12 membered bicyclic, or 10-14membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic,1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, S, B, P or Si. Heterocycloalkyl groupsmay be optionally substituted with one or more substituents. In oneembodiment, 0, 1, 2, 3, or 4 atoms of each ring of a heterocycloalkylgroup may be substituted by a substituent. Representativeheterocycloalkyl groups include piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone,morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone, 1,3-dioxolane, tetrahydrofuranyl, tetrahydrothienyl, thiirene.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,7-12 membered bicyclic, or 10-14 membered tricyclic ring systemcomprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic,or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, S,B, P or Si, wherein the nonaromatic ring system has some degree ofunsaturation. Heterocyclyl groups may be optionally substituted with oneor more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms of eachring of a heterocyclyl group may be substituted by a substituent.Examples of these groups include thiirenyl, thiadiazirinyl, dioxazolyl,1,3-oxathiolyl, 1,3-dioxolyl, 1,3-dithiolyl, oxathiazinyl, dioxazinyl,dithiazinyl, oxadiazinyl, thiadiazinyl, oxazinyl, thiazinyl,1,4-oxathiin, 1,4-dioxin, 1,4-dithiin, 1H-pyranyl, oxathiepinyl,5H-1,4-dioxepinyl, 5H-1,4-dithiepinyl,6H-isoxazolo[2,3-d]1,2,4-oxadiazolyl,7aH-oxazolo[3,2-d]1,2,4-oxadiazolyl, and the like.

The term “alkylamino” refers to an amino substituent which is furthersubstituted with one or two alkyl groups. The term “aminoalkyl” refersto an alkyl substituent which is further substituted with one or moreamino groups. The term “mercaptoalkyl” refers to an alkyl substituentwhich is further substituted with one or more mercapto groups. The term“hydroxyalkyl” or “hydroxylalkyl” refers to an alkyl substituent whichis further substituted with one or more hydroxyl groups. The term“sulfonylalkyl” refers to an alkyl substituent which is furthersubstituted with one or more sulfonyl groups. The term “sulfonylaryl”refers to an aryl substituent which is further substituted with one ormore sulfonyl groups. The term alkylcarbonyl refers to an —C(O)-alkyl.The term “mercaptoalkoxy” refers to an alkoxy substituent which isfurther substituted with one or more mercapto groups. The term“alkylcarbonylalkyl” refers to an alkyl substituent which is furthersubstituted with —C(O)-alkyl. The alkyl or aryl portion of alkylamino,aminoalkyl, mercaptoalkyl, hydroxyalkyl, mercaptoalkoxy, sulfonylalkyl,sulfonylaryl, alkylcarbonyl, and alkylcarbonylalkyl may be optionallysubstituted with one or more substituents.

As used herein the term “substituent” or “substituted” means that ahydrogen radical on a compound or group (such as, for example, alkyl,alkenyl, alkynyl, alkylene, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cyclyl, heterocycloalkyl, or heterocyclyl group) is replacedwith any desired group that do not substantially adversely affect thestability of the compound. In one embodiment, desired substituents arethose which do not adversely affect the activity of a compound. Asubstituent that substantially affects the activity of a compound is onethat causes the IC₅₀ of the compound to be greater than 100 μM. Inpreferred embodiments, a compound of the invention has an IC₅₀ in anassay or test indicative of activity useful for treatment of IL-12- orIL-23- or IL-27-related diseases or conditions. Such assays are known toone of ordinary skill in the art, and include, e.g., the assaysdescribed herein, e.g., the assays of Examples 22-25. In preferredembodiments, the assay is an assay of Example 22 and the compound has anIC₅₀ less than 1.0 mM, more preferably less than 100 μM, more preferablyless than 10 μM, more preferably less than 1 μM, more preferably lessthan 100 nM, and more preferably less than 10 nM. The term “substituted”refers to one or more substituents (which may be the same or different),each replacing a hydrogen atom. Examples of substituents include, butare not limited to, halogen (F, Cl, Br, or I), hydroxyl, amino,alkylamino, arylamino, dialkylamino, diarylamino, cyano, nitro,mercapto, oxo (i.e., carbonyl), thio, imino, formyl, carbamido,carbamyl, carboxyl, thioureido, thiocyanato, sulfoamido, sulfonylalkyl,sulfonylaryl, alkyl, alkenyl, alkoxy, mercaptoalkoxy, aryl, heteroaryl,cyclyl, heterocyclyl, wherein alkyl, alkenyl, alkyloxy, aryl,heteroaryl, cyclyl, and heterocyclyl are optionally substituted withalkyl, aryl, heteroaryl, halogen, hydroxyl, amino, mercapto, cyano,nitro, oxo (═O), thioxo (═S), or imino (═NR^(c)).

In other embodiments, substituents on any group (such as, for example,alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl,cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclyl) can be at anyatom of that group, wherein any group that can be substituted (such as,for example, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl, cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclyl)can be optionally substituted with one or more substituents (which maybe the same or different), each replacing a hydrogen atom. Examples ofsuitable substituents include, but not limited to alkyl, alkenyl,alkynyl, cyclyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro,alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, oralkoxycarbonylamino; alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl,thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, ormercaptoalkoxy.

Additional suitable substituents an alkyl, alkenyl, alkynyl, aryl,aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclyl,heterocycloalkyl, and heterocyclyl include, without limitation halogen,CN, NO₂, OR¹⁵, SR¹⁵, S(O)₂OR¹⁵, NR¹⁵R¹⁶, C₁-C₂ perfluoroalkyl, C₁-C₂perfluoroalkoxy, 1,2-methylenedioxy, (═O), (═S), (═NR¹⁵), C(O)OR¹⁵,C(O)NR¹⁵R¹⁶ OC(O)NR¹⁵R¹⁶, NR¹⁵C(O)NR¹⁵R¹⁶, C(NR¹⁶)NR¹⁵R¹⁶,NR¹⁵C(NR¹⁶)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶R¹⁷, C(O)H, C(O)R¹⁷, NR¹⁵C(O)R¹⁷,Si(R¹⁵)₃, OSi(R¹⁵)₃, Si(OH)₂R¹⁵, B(OH)₂, P(O)(OR¹⁵)₂, S(O)R¹⁷, orS(O)₂R¹⁷. Each R¹⁵ is independently hydrogen, C₁-C₆ alkyl optionallysubstituted with cycloalkyl, aryl, heterocyclyl, or heteroaryl. Each R¹⁶is independently hydrogen, C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R¹⁷ is independentlyC₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄alkyl substituted with C₃-C₆ cycloalkyl, aryl, heterocyclyl orheteroaryl. Each C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl andC₁-C₄ alkyl in each R¹⁵, R¹⁶ and R¹⁷ can optionally be substituted withhalogen, CN, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, COOH, C(O)OC₁-C₄ alkyl, NH₂,C₁-C₄ alkylamino, or C₁-C₄ dialkylamino.

As used herein, the term “lower” refers to a group having up to sixatoms. For example, a “lower alkyl” refers to an alkyl radical havingfrom 1 to 6 carbon atoms, and a “lower alkenyl” or “lower alkynyl”refers to an alkenyl or alkynyl radical having from 2 to 6 carbon atoms,respectively.

Note that unless otherwise depicted, in the groups described above thathave one point of attachment, the left atom shown in any substitutedgroup is the point of attachment.

In the compounds represented by formula (I), when n is 2 or greater, acompound of the invention may have two or more different C(R²R⁴)moieties. When there are more than one group having a designation (e.g.,R^(c)-, or R^(d)-containing substituted groups) in a compound of theinvention, the moieties (e.g., R^(c), R^(d)) can be the same ordifferent. The same rules apply to other R-groups (e.g., R, R^(a),R^(b), R^(f), R^(g), R^(h), R^(j), R^(k), etc).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., formulation into therapeuticproducts, intermediates for use in production of therapeutic compounds,isolatable or storable intermediate compounds, treating IL-12overproduction-related disorders such as rheumatoid arthritis, sepsis,Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependentdiabetes mellitus). The compounds produced by the methods herein can beincorporated into compositions, including solutions, capsules, crèmes,or ointments for administration to a subject (e.g., human, animal). Suchcompositions (e.g., pharmaceuticals) are useful for providing to thesubject desirable health or other physiological benefits that areassociated with such compounds.

The compounds of this invention include the compounds themselves, aswell as their salts, solvate, clathrate, hydrate, polymorph, orprodrugs, if applicable. As used herein, the term “pharmaceuticallyacceptable salt,” is a salt formed from, for example, an acid and abasic group of a compound of any one of the formulae disclosed herein.Illustrative salts include, but are not limited, to sulfate, citrate,acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate,phosphate, acid phosphate, isonicotinate, lactate, salicylate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, besylate, gentisinate, fumarate, gluconate,glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate(i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of any one of the formulae disclosed herein having an acidicfunctional group, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. The term “pharmaceutically acceptable salt” also refers to a saltprepared from a compound of any one of the formulae disclosed hereinhaving a basic functional group, such as an amino functional group, anda pharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude hydrogen sulfate, citric acid, acetic acid, oxalic acid,hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI),nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylicacid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid,maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid,formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term “polymorph” means solid crystalline forms of acompound of the present invention or complex thereof. Differentpolymorphs of the same compound can exhibit different physical, chemicaland/or spectroscopic properties. Different physical properties include,but are not limited to stability (e.g., to heat or light),compressibility and density (important in formulation and productmanufacturing), and dissolution rates (which can affectbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical characteristics (e.g.,tablets crumble on storage as a kinetically favored polymorph convertsto thermodynamically more stable polymorph) or both (e.g., tablets ofone polymorph are more susceptible to breakdown at high humidity).Different physical properties of polymorphs can affect their processing.For example, one polymorph might be more likely to form solvates ormight be more difficult to filter or wash free of impurities thananother due to, for example, the shape or size distribution of particlesof it.

As used herein, the term “hydrate” means a compound of the presentinvention or a salt thereof, which further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may only become active upon suchreaction under biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofany one of the formulae disclosed herein that comprise biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. Other examples ofprodrugs include derivatives of compounds of any one of the formulaedisclosed herein that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY(1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as uptake,duration of action, or onset of action; or 2) is itself biologicallyinactive but is converted in vivo to a biologically active compound.Examples of biohydrolyzable amides include, but are not limited to,lower alkyl amides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

In addition, some of the heterocyclic compounds of this invention haveone or more double bonds, or one or more asymmetric centers. Suchcompounds can occur as racemates, racemic mixtures, single enantiomers,individual diastereomers, diastereomeric mixtures, and cis- or trans- orE- or Z-double isomeric forms. All such isomeric forms of thesecompounds are expressly included in the present invention. The compoundsof this invention may also be represented in multiple tautomeric forms,in such instances, the invention expressly includes all tautomeric formsof the compounds described herein (e.g., alkylation of a ring system mayresult in alkylation at multiple sites, the invention expressly includesall such reaction products). All such isomeric forms of such compoundsare expressly included in the present invention. All crystal forms ofthe compounds described herein are expressly included in the presentinvention.

Further, the aforementioned heterocyclic compounds also include theirN-oxides. The term “N-oxides” refers to one or more nitrogen atoms, whenpresent in a heterocyclic or heteroaryl compound, are in N-oxide form,i.e., N→O. For example, in compounds of formula (I), when one of Q, U,or V is N, also included are compounds in which Q, U, or V,respectively, is N→O.

The term “inflammatory disorders” includes any inflammatory disease,disorder or condition caused, exasperated or mediated by IL-12production. Such inflammatory disorders may include, without limitation,asthma, adult respiratory distress syndrome, systemic lupuserythematosus, inflammatory bowel disease (including Crohn's disease andulcerative colitis), multiple sclerosis, insulin-dependent diabetesmellitus, autoimmune arthritis (including rheumatoid arthritis, juvenilerheumatoid arthritis, psoriatic arthritis), inflammatory pulmonarysyndrome, pemphigus vulgaris, idiopathic thrombocytopenic purpura,autoimmune meningitis, myasthenia gravis, autoimmune thyroiditis,dermatitis (including atopic dermatitis and eczematous dermatitis),psoriasis, Sjogren's Syndrome (including keratoconjunctivitis siccasecondary to Sjogren's Syndrome), alopecia areata, allergic responsesdue to arthropod bite reactions, aphthous ulcer, iritis, conjunctivitis,keratoconjunctivitis, cutaneous lupus erythematosus, scleroderma,vaginitis, proctitis, drug eruptions (such as Stevens-Johnson syndrome),leprosy reversal reactions, erythema nodosum leprosum, autoimmuneuveitis, allergic encephalomyelitis, aplastic anemia, pure red cellanemia, idiopathic thrombocytopenia, polychondritis, Wegener'sgranulomatosis, chronic active hepatitis, Graves opthalmopathy, primarybiliary cirrhosis, uveitis posterior and interstitial lung fibrosis.

“Inflammatory disorders” expressly include acute inflammatory disorders.Examples of acute inflammatory disorders include graft versus hostdisease, transplant rejection, septic shock, endotoxemia, Lymearthritis, infectious meningitis (e.g., viral, bacterial, Lymedisease-associated), an acute episode of asthma and acute episodes of anautoimmune disease.

“Inflammatory disorders” expressly include chronic inflammatorydisorders. Nonlimiting examples of chronic inflammatory disorder includeasthma, rubella arthritis, and chronic autoimmune diseases, such assystemic lupus erythematosus, psoriasis, inflammatory bowel disease,including Crohn's disease and ulcerative colitis, multiple sclerosis andrheumatoid arthritis.

The term “immune diseases” includes any immune disease, disorder orcondition caused, exasperated or mediated by IL-12 production. Suchimmune diseases may include, without limitation, rheumatoid arthritis,juvenile rheumatoid arthritis, systemic onset juvenile rheumatoidarthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer,seronegative arthropathies, osteoarthritis, inflammatory bowel disease,ulcerative colitis, systemic lupus erythematosis, antiphospholipidsyndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonaryfibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis,orchitis/vasectomy reversal procedures, allergic/atopic diseases,asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergicconjunctivitis, hypersensitivity pneumonitis, transplants, organtransplant rejection, graft-versus-host disease, systemic inflammatoryresponse syndrome, sepsis syndrome, gram positive sepsis, gram negativesepsis, culture negative sepsis, fungal sepsis, neutropenic fever,urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiationexposure, acute pancreatitis, adult respiratory distress syndrome,rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatorypathologies, sarcoidosis, Crohn's pathology, sickle cell anemia,diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergicrhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis,asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia,hemolytic disesease, thrombocytopenia, graft rejection of any organ ortissue, kidney translplant rejection, heart transplant rejection, livertransplant rejection, pancreas transplant rejection, lung transplantrejection, bone marrow transplant (BMT) rejection, skin allograftrejection, cartilage transplant rejection, bone graft rejection, smallbowel transplant rejection, fetal thymus implant rejection, parathyroidtransplant rejection, xenograft rejection of any organ or tissue,allograft rejection, anti-receptor hypersensitivity reactions, Gravesdisease, Raynoud's disease, type B insulin-resistant diabetes, asthma,myasthenia gravis, antibody-meditated cytotoxicity, type IIIhypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), polyneuropathy, organomegaly,endocrinopathy, monoclonal gammopathy, skin changes syndrome,antiphospholipid syndrome, pemphigus, scleroderma, mixed connectivetissue disease, idiopathic Addison's disease, diabetes mellitus, chronicactive hepatitis, primary billiary cirrhosis, vitiligo, vasculitis,post-MI cardiotomy syndrome, type IV hypersensitivity, contactdermatitis, hypersensitivity pneumonitis, allograft rejection,granulomas due to intracellular organisms, drug sensitivity,metabolic/idiopathic, Wilson's disease, hemachromatosis,alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto'sthyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axisevaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis,cachexia, cystic fibrosis, neonatal chronic lung disease, chronicobstructive pulmonary disease (COPD), familial hematophagocyticlymphohistiocytosis, dermatologic conditions, psoriasis, alopecia,nephrotic syndrome, nephritis, glomerular nephritis, acute renalfailure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy,anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy(e.g., including but not limited toasthenia, anemia, cachexia, and thelike), chronic salicylate intoxication, and the like. See, e.g., theMerck Manual, 12th-17th Editions, Merck & Company, Rahway, N.J. (1972,1977, 1982, 1987, 1992, 1999), Pharmacotherapy Handbook, Wells et al.,eds., Second Edition, Appleton and Lange, Stamford, Conn. (1998, 2000),each entirely incorporated by reference.

The term “bone loss disease” includes any bone loss disease, disorder orcondition caused, exasperated or mediated by IL-12 production e.g.,periodontal disease, non-malignant bone disorders (e.g., osteoporosis,Paget's disease of bone, osteogenesis imperfecta, fibrous dysplasia, andprimary hyperparathyroidism), estrogen deficiency, inflammatory boneloss, bone malignancy, arthritis, osteopetrosis, and certaincancer-related disorders (e.g., hypercalcemia of malignancy (HCM),osteolytic bone lesions of multiple myeloma and osteolytic bonemetastases of breast cancer and other metastatic cancers.

The term “neurological disorder” includes any neurological disease,disorder or condition caused, exasperated or mediated by IL-12production. Such neurological disorders may include, without limitation,neurodegenerative diseases, multiple sclerosis, migraine headache, AIDSdementia complex, demyelinating diseases, such as multiple sclerosis andacute transverse myelitis; extrapyramidal and cerebellar disorders' suchas lesions of the corticospinal system; disorders of the basal gangliaor cerebellar disorders; hyperkinetic movement disorders such asHuntington's Chorea and senile chorea; drug-induced movement disorders,such as those induced by drugs which block CNS dopamine receptors;hypokinetic movement disorders, such as Parkinson's disease; Progressivesupranucleo Palsy; structural lesions of the cerebellum; spinocerebellardegenerations, such as spinal ataxia, Friedreich's ataxia, cerebellarcortical degenerations, multiple systems degenerations (Mencel,Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders(Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, andmitochondrial multi.system disorder); demyelinating core disorders, suchas multiple sclerosis, acute transverse myelitis; and disorders of themotor unit such as neurogenic muscular atrophies (anterior horn celldegeneration, such as amyotrophic lateral sclerosis, infantile spinalmuscular atrophy and juvenile spinal muscular atrophy); Alzheimer'sdisease; Down's Syndrome in middle age; Diffuse Lewy body disease;Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronicalcoholism; Creutzfeldt-Jakob disease; Subacute sclerosingpanencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica,and the like. Such a method can optionally comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising at least one TNF antibody or specified portion or variant toa cell, tissue, organ, animal or patient in need of such modulation,treatment or therapy. See, e.g., the Merck Manual, 16, Edition, Merck &Company, Rahway, N.J. (1992)

In the case of overlap in these definitions, the disease, condition ordisorder may be considered to be a member of any of the above listedclasses of IL-12 production-related disorders.

In still another aspect, the present invention features a method fortreating an IL-12 production-related disorder (e.g., rheumatoidarthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, orinsulin-dependent diabetes mellitus). The method includes administeringto a subject (e.g., a human or an animal) in need thereof an effectiveamount of one or more compounds of formula (I) or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, polymorph or prodrugthereof, or a pharmaceutical composition having an effective amount ofone or more compounds of formula (I) or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymorph or prodrug thereof. Themethod can also include the step of identifying that the subject is inneed of treatment of diseases or disorders described above. Theidentification can be in the judgment of a subject or a healthprofessional and can be subjective (e.g., opinion) or objective (e.g.,measurable by a test or a diagnostic method).

In one aspect, this invention features a method for treating orpreventing disorders associated with excessive bone loss, e.g.,periodontal disease, non-malignant bone disorders (e.g., osteoporosis,Paget's disease of bone, osteogenesis imperfecta, fibrous dysplasia, andprimary hyperparathyroidism), estrogen deficiency, inflammatory boneloss, bone malignancy, arthritis, osteopetrosis, and certaincancer-related disorders (e.g., hypercalcemia of malignancy (HCM),osteolytic bone lesions of multiple myeloma and osteolytic bonemetastases of breast cancer and other metastatic cancers). The methodincludes administering to a subject (e.g., a human or an animal) in needthereof an effective amount of one or more compounds of formula (I) or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, or a pharmaceutical composition having an effective amount ofone or more compounds of formula (I) or a pharmaceutically acceptablesalt, solvate, clathrate, or prodrug thereof. The method can alsoinclude the step of identifying that the subject is in need of treatmentof diseases or disorders described above. The identification can be inthe judgment of a subject or a health professional and can be subjective(e.g., opinion) or objective (e.g., measurable by a test or a diagnosticmethod).

In another aspect, this invention features methods for inhibitingosteoclast formation in vitro or in vivo. The method includes contactinga pre-osteoclast cell (e.g., a cell capable of forming an osteoclastcell upon differentiation and/or fusion) with an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt, solvate,clathrate, or prodrug thereof or a pharmaceutical composition comprisingan effective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, polymorph or prodrugthereof.

In a further aspect, this invention features methods of treating orpreventing a disorder associated with excessive bone resorption byosteoclasts in a subject in need thereof. The method includesadministering to a subject (e.g., a human or an animal) in need thereofan effective amount of one or more compounds of formula (I) or apharmaceutically acceptable salt, solvate, clathrate, or prodrugthereof, or a pharmaceutical composition having an effective amount ofone or more compounds of formula (I) or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymorph or prodrug thereof. Themethod can also include the step of identifying that the subject is inneed of treatment of diseases or disorders described above. Theidentification can be in the judgment of a subject or a healthprofessional and can be subjective (e.g., opinion) or objective (e.g.,measurable by a test or a diagnostic method).

Also within the scope of this invention are a composition containing oneor more of the pyridine compounds described above for use in treating anIL-12 production-related disorder (e.g., rheumatoid arthritis, sepsis,Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependentdiabetes mellitus), treating or preventing disorders associated withexcessive bone loss, e.g., periodontal disease, non-malignant bonedisorders (e.g., osteoporosis, Paget's disease of bone, osteogenesisimperfecta, fibrous dysplasia, and primary hyperparathyroidism) estrogendeficiency, inflammatory bone loss, bone malignancy, arthritis,osteopetrosis, and certain cancer-related disorders (e.g., hypercalcemiaof malignancy (HCM), osteolytic bone lesions of multiple myeloma andosteolytic bone metastases of breast cancer and other metastaticcancers), inhibiting osteoclast formation in vitro or in vivo, ortreating or preventing a disorder associated with excessive boneresorption by osteoclasts) and the use of such a composition for themanufacture of a medicament for the just-described use.

The compounds described above can be prepared by methods describedherein, some of which are known in the art. For example, a pyridinecompound can be prepared by using 2,4,6-trichloro-pyridine as a startingmaterial. The three chloro groups can be displaced by varioussubstitutents. More specifically, a first chloro group (e.g., atposition 2 or position 4) can react with, e.g., morpholine, to form amorpholinyl pyridine, e.g., compounds A and B in Scheme 1 below. Thedesired isomeric product can be separated from others by, e.g., highperformance liquid chromatography or flash chromatography. A secondchloro group can be replaced by reacting with a nucleophile, such as analcohol in the presence of base, e.g., sodium hydride, to provide, e.g.,compounds C and D in Scheme 1 below. In other examples, a compound offormula (I), wherein Y is CH₂ (e.g., Compound 1), can be prepared byreacting the pyridine chloride with a Grignard reagent, an organotinreagent, an organocopper reagent, an organoboric acid, or an organozincreagent in the presence of an organopalladium compound as a catalyst.Isomeric forms may be produced. The desired isomeric product can beseparated from others by, e.g., high performance liquid chromatography.A third chloro group undergoes a displacement reaction with, e.g.,hydrazine, to afford, e.g., compound E in Scheme 1, and the primaryamine of the coupled hydrazine moiety further reacts with an aldehyde,e.g., indole-3-carboxaldehyde to form a hydrazone linkage, e.g.,compound 1 in Scheme 1. Thus, a pyridine compound of this invention isobtained. If preferred, other types of linkages can be prepared bysimilar reactions. Sensitive moieties on a pyridinyl intermediate and anucleophile can be protected prior to coupling. A pyridine compound canalso be prepared via a palladium mediated amination of a chlorosubstituted pyridine starting material. For example,5-amino-2,3-dimethylindole and4-{2-chloro-6-[2-(3,4-dimethoxy-phenyl)-pyridin-4-yl}-morpholine can becoupled in the presence of palladium acetate, binap, and cesiumcarbonate in refluxing toluene to provide compound 4.

The chemicals used in the above-described synthetic routes may include,for example, solvents, reagents, catalysts, and protecting group anddeprotecting group reagents. The methods described above may alsoadditionally include steps, either before or after the steps describedspecifically herein, to add or remove suitable protecting groups inorder to ultimately allow synthesis of the pyridine compounds. Inaddition, various synthetic steps may be performed in an alternatesequence or order to give the desired compounds. Synthetic chemistrytransformations and protecting group methodologies (protection anddeprotection) useful in synthesizing applicable pyridine compounds areknown in the art and include, for example, those described in R, Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995) and subsequent editions thereof.

A pyridine compound thus obtained can be further purified by flashcolumn chromatography, high performance liquid chromatography, orcrystallization.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Alkylating agents are any reagent that is capable of effecting thealkylation of the functional group at issue (e.g., oxygen atom of analcohol, nitrogen atom of an amino group). Alkylating agents are knownin the art, including in the references cited herein, and include alkylhalides (e.g., methyl iodide, benzyl bromide or chloride), alkylsulfates (e.g., methyl sulfate), or other alkyl group-leaving groupcombinations known in the art. Leaving groups are any stable speciesthat can detach from a molecule during a reaction (e.g., eliminationreaction, substitution reaction) and are known in the art, including inthe references cited herein, and include halides (e.g., I—, Cl—, Br—,F—), hydroxy, alkoxy (e.g., —OMe, —O-t-Bu), acyloxy anions (e.g., —OAc,—OC(O)CF₃), sulfonates (e.g., mesyl, tosyl), acetamides (e.g.,—NHC(O)Me), carbamates (e.g., N(Me)C(O)Ot-Bu), phosphonates (e.g.,—OP(O)(OEt)₂), water or alcohols (protic conditions), and the like.

Nucleophilic agents are known in the art and are described in thechemical texts and treatises referred to herein. The chemicals used inthe aforementioned methods may include, for example, solvents, reagents,catalysts, protecting group and deprotecting group reagents and thelike. The methods described above may also additionally include steps,either before or after the steps described specifically herein, to addor remove suitable protecting groups in order to ultimately allowsynthesis of the compound of the formulae described herein. The methodsdelineated herein contemplate converting compounds of one formula tocompounds of another formula. The process of converting refers to one ormore chemical transformations, which can be performed in situ, or withisolation of intermediate compounds. The transformations can includereacting the starting compounds or intermediates with additionalreagents using techniques and protocols known in the art, includingthose in the references cited herein. Intermediates can be used with orwithout purification (e.g., filtration, distillation, crystallization,chromatography). Other embodiments relate to the intermediate compoundsdelineated herein, and their use in the methods (e.g., treatment,synthesis) delineated herein.

The compounds and compositions described herein are useful to treat andprevent any IL-12 production-related disorders, e.g., inflammatorydisorders, immune diseases, and bone loss diseases. The method involvesadministering an effective amount of a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate,polymorph, or prodrug thereof, to a subject in need of treatment ofIL-12 overproduction related diseases

As used herein, the term “effective amount” refers to an amount of acompound of this invention which is sufficient to reduce or amelioratethe severity, duration, progression, or onset of an inflammatorydisorder, immune diseases, or bone loss disease, prevent the advancementof an inflammatory disorder, immune diseases, or bone loss disease,cause the regression of an inflammatory disorder, immune diseases, orbone loss disease, prevent the recurrence, development, onset orprogression of a symptom associated with an inflammatory disorder,immune diseases, or bone loss disease, or enhance or improve theprophylactic or therapeutic effect(s) of another therapy. In certainpreferred embodiments, treatment according to the invention provides areduction in or prevention of at least one symptom or manifestation ofan IL-12-, IL-23-, or IL-27-related disorder (e.g., inflammatorydisorder, immune diseases, or bone loss disease), as determined in vivoor in vitro of at least about 10%, more preferably 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, 98% or 99%.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.An effective amount of the pyridine compound of this invention can rangefrom about 0.001 mg/kg to about 1000 mg/kg, more preferably 0.01 mg/kgto about 100 mg/kg, more preferably 0.1 mg/kg to about 10 mg/kg; or anyrange in which the low end of the range is any amount between 0.001mg/kg and 900 mg/kg and the upper end of the range is any amount between0.1 mg/kg and 1000 mg/kg (e.g., 0.005 mg/kg and 200 mg/kg, 0.5 mg/kg and20 mg/kg). Effective doses will also vary, as recognized by thoseskilled in the art, depending on the diseases treated, route ofadministration, excipient usage, and the possibility of co-usage withother therapeutic treatments such as use of other agents.

To practice the method of the present invention, a compound disclosedherein, as a component of a pharmaceutical composition, can beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous,intracutaneous, intravenous, intramuscular, intraarticular,intraarterial, intrasynovial, intrasternal, intrathecal, intralesionaland intracranial injection or infusion techniques.

A sterile injectable composition, for example, a sterile injectableaqueous or oleaginous suspension, can be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation can also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspending medium(e.g., synthetic mono- or diglycerides). Fatty acids, such as oleic acidand its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions can also contain a long-chain alcoholdiluent or dispersant, or carboxymethyl cellulose or similar dispersingagents. Other commonly used surfactants such as Tweens or Spans or othersimilar emulsifying agents or bioavailability enhancers which arecommonly used in the manufacture of pharmaceutically acceptable solid,liquid, or other dosage forms can also be used for the purposes offormulation.

A composition for oral administration can be any orally acceptabledosage form including, but not limited to, capsules, tablets, emulsionsand aqueous suspensions, dispersions and solutions. In the case oftablets for oral use, carriers which are commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried corn starch. When aqueous suspensionsor emulsions are administered orally, the active ingredient can besuspended or dissolved in an oily phase combined with emulsifying orsuspending agents. If desired, certain sweetening, flavoring, orcoloring agents can be added. A nasal aerosol or inhalation compositioncan be prepared according to techniques well-known in the art ofpharmaceutical formulation and can be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or othersolubilizing or dispersing agents known in the art. A heterocycliccompound of this invention can also be administered in the form ofsuppositories for rectal administration.

The carrier in the pharmaceutical composition must be “acceptable” inthe sense of being compatible with the active ingredient of theformulation (and preferably, capable of stabilizing it) and notdeleterious to the subject to be treated. For example, solubilizingagents such as cyclodextrins, which form specific, more solublecomplexes with the compounds of this invention, or one or moresolubilizing agents, can be utilized as pharmaceutical excipients fordelivery of the heterocyclic compounds. Examples of other carriersinclude colloidal silicon dioxide, magnesium stearate, cellulose, sodiumlauryl sulfate, and D&C Yellow # 10.

In certain embodiments, pharmaceutical compositions and dosage forms ofthe invention comprise one or more active ingredients in relativeamounts and formulated in such a way that a given pharmaceuticalcomposition or dosage form inhibits the uptake of calcium. Preferredpharmaceutical compositions and dosage forms comprise a compound offormula (I), or a pharmaceutically acceptable prodrug, salt, solvate, orclathrate thereof, optionally in combination with one or more additionalactive agents.

The methods for treating or preventing disorders associated withexcessive bone loss in a patient in need thereof can further compriseadministering to the patient being administered a compound of thisinvention, an effective amount of one or more other therapeutic agents.Such therapeutic agents may include other therapeutic agents such asthose conventionally used to prevent or treat disorders associated withexcessive bone resorption or symptoms thereof. For example, such otheragents include anti-resorptive agents for example progestins,polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists,estrogen (such as Premarin®), estrogen/progestin combinations, andestrogen derivatives (such as estrone, estriol or 17α, 17β-ethynylestradiol).

In such combination therapy treatment, both the compounds of thisinvention and the other drug agent(s) are administered to mammals (e.g.,humans, male or female) by conventional methods. The agents may beadministered in a single dosage form or in separate dosage forms.Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective-amount range. In one embodiment of the invention where anothertherapeutic agent is administered to an animal, the effective amount ofthe compound of this invention is less than its effective amount wouldbe where the other therapeutic agent is not administered. In anotherembodiment, the effective amount of the conventional agent is less thanits effective amount would be where the compound of this invention isnot administered. In this way, undesired side effects associated withhigh doses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

Exemplary progestins are available from commercial sources and include:algestone acetophenide, altrenogest, amadinone acetate, anagestoneacetate, chlormadinone acetate, cingestol, clogestone acetate,clomegestone acetate, delmadinone acetate, desogestrel, dimethisterone,dydrogesterone, ethynerone, dthynodiol diacetate, etonogestrel,fluorogestone acetate, gestaclone, gestodene, gestonorone caproate,gestrinone, haloprogesterone, hydroxyprogesterone, caproate,levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate,melengestrol acetate, methynodiol diacetate, norethindrone,norethindrone acetate, norethynodrel, norgestimate, norgestomet,norgestrel, oxogestone phenpropionate, progesterone, quingestanolacetate, quingestrone, and tigestol. Preferred progestins aremedroxyprogestrone, norethindrone and norethynodrel.

Exemplary bone resorption inhibiting polyphosphonates includepolyphosphonates of the type disclosed in U.S. Pat. No. 3,683,080.Preferred polyphosphonates are geminal dipolyphosphonates (also referredto as bis-phosphonates). Tiludronate disodium is an especially preferredpolyphosphonate. Ibandronic acid is an especially preferredpolyphosphonate. Alendronate is an especially preferred polyphosphonate.Zoledronic acid is an especially preferred polyphosphonate. Otherpreferred polyphosphonates are 6-amino-1-hydroxy-hexylidene-biphosphonicacid and 1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid.The polyphosphonates may be administered in the form of the acid, or ofa soluble alkali metal salt or alkaline earth metal salt. Hydrolyzableesters of the polyphosphonates are likewise included. Specific examplesinclude ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonicacid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichlorodiphosphonic acid, methane hydroxy diphosphonic acid,ethane-1-amino-1,1-diphosphonic acid, ethane-2-amino-1,1-diphosphonicacid, propane-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenylamino methane diphosphonic acid, N,N-dimethylamino methane diphosphonicacid, N(2-hydroxyethyl)amino methane diphosphonic acid,butane-4-amino-1-hydroxy-1,1-diphosphonic acid,pentane-5-amino-1-hydroxy-1,1-diphosphonic acid,hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceuticallyacceptable esters and salts thereof.

In particular, the compounds of this invention may be combined with amammalian estrogen agonist/antagonist. Any estrogen agonist/antagonistmay be used for this purpose. The term estrogen agonist/antagonistrefers to compounds which bind with the estrogen receptor, inhibit boneturnover and/or prevent bone loss. In particular, estrogen agonists areherein defined as chemical compounds capable of binding to the estrogenreceptor sites in mammalian tissue, and mimicking the actions ofestrogen in one or more tissue. Estrogen antagonists are herein definedas chemical compounds capable of binding to the estrogen receptor sitesin mammalian tissue; and blocking the actions of estrogen in one or moretissues. Such activities are readily determined by those skilled in theart of standard assays including estrogen receptor binding assays,standard bone histomorphometric and densitometer methods, and E. FEriksen et al., Bone Histomorphometry, Raven Press, New York, pp. 1-74(1994); S. J. Grier et. al., The Use of Dual-Energy X-Ray AbsorptiometryIn Animals, Inv. Radiol. 31(1): 50-62 (1996); Wahner H. W. and FogelmanI., The Evaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry inClinical Practice., Martin Dunitz Ltd., London, pp. 1-296 (1994)). Avariety of these compounds are described and referenced below.

A preferred estrogen agonist/antagonist is droloxifene: (phenol,3-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenyl-1-butenyl)-, (E)-) andrelated compounds which are disclosed in U.S. Pat. No. 5,047,431.Another preferred estrogen agonist/antagonist is3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid, which is disclosedin Wilson et al., Endocrinology 138: 3901-11 (1997). Another preferredestrogen agonist/antagonist is tamoxifen:(ethanamine,2-(−4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-,2-hydroxy-1,2,3-propanetricarboxylate(1:1)) and related compounds whichare disclosed in U.S. Pat. No. 4,536,516. Another related compound is4-hydroxy tamoxifen which is disclosed in U.S. Pat. No. 4,623,660.

A preferred estrogen agonist/antagonist is raloxifene: (methanone,(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)ethoxy)phenyl)hydrochloride) which is disclosed in U.S. Pat. No. 4,418,068.Another preferred estrogen agonist/antagonist is toremifene:(ethanamine,2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-,2-hydroxy-1,2,3-propanetricarboxylate (1:1) which is disclosed in U.S.Pat. No. 4,996,225. Another preferred estrogen agonist/antagonist iscentchroman:1-(2-((4-(-methoxy-2,2,dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-pyrrolidine,which is disclosed in U.S. Pat. No. 3,822,287. Also preferred islevormeloxifene. Another preferred estrogen agonist/antagonist isidoxifene:(E)-1-(2-(4-(1-(4-iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrrolidinone,which is disclosed in U.S. Pat. No. 4,839,155. Another preferredestrogen agonist/antagonist is2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-olwhich is disclosed in U.S. Pat. No. 5,488,058. Another preferredestrogen agonist/antagonist is6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2-olwhich is disclosed in U.S. Pat. No. 5,484,795. Another preferredestrogen agonist/antagonist is(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hydroxy-phenyl)-benzo[b]thiophen-3-yl)-methanonewhich is disclosed, along with methods of preparation, in PCTpublication no. WO 95/10513 assigned to Pfizer Inc. Other preferredestrogen agonist/antagonists include compounds as described in U.S. Pat.No. 5,552,412. Especially preferred compounds described therein are:cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;(−)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol;cis-1-(6′-pyrrolodinoethoxy-3′-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene;1-(4′-pyrrolidinoethoxyphenyl)-2-(4″-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-naphthalene-2-ol; and1-(4′-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline.Other estrogen agonist/antagonists are described in U.S. Pat. No.4,133,814. U.S. Pat. No. 4,133,814 discloses derivatives of2-phenyl-3-aroyl-benzothiophene and2-phenyl-3-aroylbenzothiophene-1-oxide.

Those skilled in the art will recognize that other bone anabolic agents,also referred to as bone mass augmenting agents, may be used inconjunction with the compounds of this invention. A bone mass augmentingagent is a compound that augments bone mass to a level which is abovethe bone fracture threshold as detailed in the World Health OrganizationStudy World Health Organization, “Assessment of Fracture Risk and itsApplication to Screening for Postmenopausal Osteoporosis (1994). Reportof a WHO Study Group. World Health Organization Technical Series 843.”Any prostaglandin, or prostaglandin agonist/antagonist may be used incombination with the compounds of this invention. Those skilled in theart will recognize that IGF-1, sodium fluoride, parathyroid hormone(PTH), active fragments of parathyroid hormone, growth hormone or growthhormone secretagogues may also be used. The following paragraphsdescribes in greater detail exemplary compounds that may be administeredin combination with compounds of this invention

Prostaglandins: The term prostaglandin refers to compounds which areanalogs of the natural prostaglandins PGD₁, PGD₂, PGE₂, PGE₁ and PGF₂which are useful in the treatment of osteoporosis and other disordersassociated with excessive osteoclastic bone resorption. These compoundsbind to the prostaglandins receptors. Such binding is readily determinedby those skilled in the art of standard assays (e.g., S. An et al.,Cloning and Expression of the EP₂ Subtype of Human Receptors forProstaglandin E₂ Biochemical and Biophysical Research Communications,197(1): 263-270 (1993)).

Prostaglandins are alicyclic compounds related to the basic compoundprostanoic acid. The carbon atoms of the basic prostaglandin arenumbered sequentially from the carboxylic carbon atom through thecyclopentyl ring to the terminal carbon atom on the adjacent side chain.Normally the adjacent side chains are in the trans orientation. Thepresence of an oxo group at C-9 of the cyclopentyl moiety is indicativeof a prostaglandin within the E class while PGE₂ contains a transunsaturated double bond at the C₁₃-C₁₄ and a cis double bond at theC₅-C₆ position.

A variety of prostaglandins are described and referenced below. However,other prostaglandins will be known to those skilled in the art.Exemplary prostaglandins are disclosed in U.S. Pat. Nos. 4,171,331 and3,927,197. Norrdin et al., The Role of Prostaglandins in Bone in Vivo,Prostaglandins Leukotriene Essential Fatty Acids 41: 139-150 (1990) is areview of bone anabolic prostaglandins. Any prostaglandinagonist/antagonist may be used in combination with the compounds of thisinvention. The term prostaglandin agonist/antagonist refers to compoundswhich bind to prostaglandin receptors (eg., An S. et al., Cloning andExpression of the EP₂ Subtype of Human Receptors for Prostaglandin E₂,Biochemical and Biophysical Research Communications 197(1): 263-70(1993)) and mimic the action of prostaglandin in vivo (e.g., stimulatebone formation and increase bone mass). Such actions are readilydetermined by those skilled in the art of standard assays. Eriksen E. F.et al., Bone Histomorphometry, Raven Press, New York, 1994, pp. 1-74; S.J. Grier et al., The Use of Dual-Energy X-Ray Absorptiometry In Animals,Inv. Radiol. 31(1): 50-62 (1996); H. W. Wahner and I. Fogelman, TheEvaluation of Osteoporosis: Dual Energy X-Ray Absorptiometry in ClinicalPractice, Martin Dunitz Ltd. London, pp. 1-296 (1994). A number of thesecompounds are described and reference below. However, otherprostaglandin agonists/antagonists will be known to those skilled in theart. Exemplary prostaglandin agonists/antagonists are disclosed asfollows. U.S. Pat. No. 3,932,389 discloses2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-omega-pentanorprostaglandinsuseful for bone formation activity. U.S. Pat. No. 4,018,892, discloses16-aryl-13,14-dihydro-PGE₂ p-biphenyl esters useful for bone formationactivity. U.S. Pat. No. 4,219,483, discloses 2,3,6-substituted-4-pyronesuseful for bone formation activity. U.S. Pat. No. 4,132,847, discloses2,3,6-substituted-4-pyrones useful for bone formation activity. U.S.Pat. No. 4,000,309, discloses 16-aryl-13,14-dihydro-PGE₂ p-biphenylesters useful for bone formation activity. U.S. Pat. No. 3,982,016,discloses 16-aryl-13,14-dihydro-PGE₂ p-biphenyl esters useful for boneformation activity. U.S. Pat. No. 4,621,100, discloses substitutedcyclopentanes useful for bone formation activity. U.S. Pat. No.5,216,183, discloses cyclopentanones useful for bone formation activity.

Sodium fluoride may be used in combination with the compounds of thisinvention. The term sodium fluoride refers to sodium fluoride in all itsforms (e.g., slow release sodium fluoride, sustained release sodiumfluoride). Sustained release sodium fluoride is disclosed in U.S. Pat.No. 4,904,478. The activity of sodium fluoride is readily determined bythose skilled in the art of biological protocols.

Bone morphogenetic protein may be used in combination with the compoundsof this invention (e.g., see Ono et al., Promotion of the OsteogeneticActivity of Recombinant Human Bone Morphogenetic Protein byProstaglandin E₁, Bone 19(6): 581-588 (1996)).

Any parathyroid hormone (PTH) may be used in combination with thecompound of this invention. The term parathyroid hormone refers toparathyroid hormone, fragments or metabolites thereof and structuralanalogs thereof which can stimulate bone formation and increase bonemass. Also included are parathyroid hormone related peptides and activefragments and analogs of parathyroid related peptides (see PCTpublication No. WO 94/01460). Such bone anabolic functional activity isreadily determined by those skilled in the art of standard assays. Avariety of these compounds are described and referenced below. However,other parathyroid hormone will be known to those skilled in the art.Exemplary parathyroid hormones are disclosed in the followingreferences. “Human Parathyroid Peptide Treatment of VertebralOsteoporosis”, Osteoporosis Int., 3, (Supp 1): 199-203. “PTH 1-34Treatment of Osteoporosis with Added Hormone Replacement Therapy:Biochemical, Kinetic and Histological Responses” Osteoporosis Int. 1:162-170.

Any growth hormone or growth hormone secretagogue may be used incombination with the compounds of this invention. The term growthhormone secretagogue refers to a compound which stimulates the releaseof growth hormone or mimics the action of growth hormone (e.g.,increases bone formation leading to increased bone mass). Such actionsare readily determined by those skilled in the art of standard assayswell known to those of skill in the art. A variety of these compoundsare disclosed in the following published PCT patent applications: WO95/14666; WO 95/13069; WO 94/19367; WO 94/13696; and WO 95/34311.However, other growth hormones or growth hormone secretagogues will beknown to those skilled in the art. In particular, a preferred growthhormone secretagogue isN-[1(R)-[1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4′-piperidin]-1′-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide:MK-667. Other preferred growth hormone secretagogues include2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramideor its L-tartaric acid salt;2-amino-N-(1-(R)-benzyloxymethyl-2-(3a-(R)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-2-oxo-ethyl)isobutyramide;2-amino-N-(2-(3a-(R)-benzyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)benzyloxymethyl-2-oxo-ethyl)isobutyramide;and2-amino-N-(1-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.

The other therapeutic agent can be a steroid or a non-steroidalanti-inflammatory agent. Useful non-steroidal anti-inflammatory agents,include, but are not limited to, aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam; salicylic acidderivatives, including aspirin, sodium salicylate, choline magnesiumtrisalicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, and olsalazin; para-aminophennol derivatives includingacetaminophen and phenacetin; indole and indene acetic acids, includingindomethacin, sulindac, and etodolac; heteroaryl acetic acids, includingtolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates),including mefenamic acid, and meclofenamic acid; enolic acids, includingoxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone,oxyphenthartazone); and alkanones, including nabumetone andpharmaceutically acceptable salts thereof and mixtures thereof. For amore detailed description of the NSAIDs, see Paul A. Insel,Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed inthe Treatment of Gout, in Goodman & Gilman's The Pharmacological Basisof Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds.,9^(th) ed 1996) and Glen R, Hanson, Analgesic, Antipyretic andAnti-Inflammatory Drugs in Remington: The Science and Practice ofPharmacy Vol II 1196-1221 (A. R. Gennaro ed. 19th ed. 1995) which arehereby incorporated by reference in their entireties.

For arthritis, inflammation-mediated bone loss and other disorders thathave an inflammatory component, preferred conventional treatments foruse in combination therapy with the compounds and compositions of thisinvention include (without limitation) naproxen sodium (Anaprox® andAnaprox® DS, Roche), flurbiprofen (Ansaid®; Pharmacia), diclofenacsodium+misoprostil (Arthrotec®, Searle), valdecoxib (Bextra®,Pharmacia), diclofenac potassium (Cataflam® and Voltaren®, Novartis),celecoxib (Celebrex®, Pharmacia), sulindac (Clinoril®, Merck), oxaprozin(Daypro®, Pharmacia), salsalate (Disalcid®, 3M), diflunisal (Dolobid®,Merck), naproxen sodium (EC Naprosyn®, Roche), piroxicam (Feldene®,Pfizer), indomethacin (Indocin® and Indocin SR®, Merck), etodolac(Lodine® and Lodine XL®, Wyeth), meloxicam (Mobic®, BoehringerIngelheim), ibuprofen (Motrin®, Pharmacia), naproxen (Naprelan®, Elan),naproxen (Naprosyn®, Roche), ketoprofen (Orudis® and Oruvail®, Wyeth),nabumetone (Relafen®, SmithKline), tolmetin sodium (Tolectin®, McNeil),choline magnesium trisalicylate (Trilisate®, Purdue Fredrick), androfecoxib (Vioxx®, Merck).

In any case where pain in a component of the target disorder, the othertherapeutic agent can be an analgesic. Useful analgesics include, butare not limited to, phenacetin, butacetin, acetaminophen, nefopam,acetoamidoquinone, and mixtures thereof.

For use against osteoporosis, Paget's disease and other disordersassociated with bone deterioration, preferred conventional agents thatmay be used in combination with compounds and compositions of thisinvention include (without limitation) bisphosphonates (such asetidronate (Didronel®, Procter & Gamble), pamidronate (Aredia®,Novartis), and alendronate (Fosamax®, Merck)), tiludronate (Skelid®,Sanofi-Synthelabo, Inc.), risedronate (Actonel®, Procter &Gamble/Aventis), calcitonin (Miacalcin®), estrogens (Climara®, Estrace®,Estraderm®, Estratab®, Ogen®, Ortho-Est®, Vivelle®, Premarin®, andothers) estrogens and progestins (Activella™, FemHrt®, Premphase®,Prempro®, and others), parathyroid hormone and portions thereof, such asteriparatide (Forteo®, Eli Lilly and Co.), selective estrogen receptormodulators (SERMs) (such as raloxifene (Evista®)) and treatmentscurrently under investigation (such as other parathyroid hormones,sodium fluoride, vitamin D metabolites, and other bisphosphonates andselective estrogen receptor modulators).

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising at least one compound of this invention to a cell, tissue,organ, animal or patient in need of such modulation, treatment ortherapy. Such a method can optionally further comprise co-administrationor combination therapy for treating an IL-12 production relateddisorder, wherein the administering further comprises administeringbefore, concurrently with, and/or after the compound of this invention,at least one additional active agent selected from a TNF antagonist(e.g., but not limited to a TNF antibody or fragment, a soluble TNFreceptor or fragment, fusion proteins thereof, or a small molecule TNFantagonist), an antirheumatic (e.g., methotrexate, auranofin,aurothioglucose, azathioprine, etanercept, gold sodium thiomalate,hydroxychloroquine sulfate, leflunomide, sulfasalzine), a musclerelaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), ananalgesic, an anesthetic, a sedative, a local anethetic, a neuromuscularblocker, an antimicrobial (e.g., aminoglycoside, an antifungal, anantiparasitic, an antiviral, a carbapenem, cephalosporin, afluororquinolone, a macrolide, a penicillin, a sulfonamide, atetracycline, another antimicrobial), an antipsoriatic, acorticosteriod, an anabolic steroid, a diabetes related agent, amineral, a nutritional, a thyroid agent, a vitamin, a calcium relatedhormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer,a laxative, an anticoagulant, an erythropieitin (e.g., epoetin alpha), afilgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a growth hormone, a hormonereplacement drug, an estrogen receptor modulator, a mydriatic, acycloplegic, an alkylating agent, an antimetabolite, a mitoticinhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, anantipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, astimulant, donepezil, tacrine, an asthma medication, a beta agonist, aninhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn,an epinephrine or analog, domase alpha (Pulmozyme), a cytokine or acytokine antagonistm. Suitable dosages are well known in the art. See,e.g., Wells et al., eds., Pharmacotherapy Handbook, 2.sup.nd Edition,Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, TarasconPocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, LomaLinda, Calif. (2000), each of which references are entirely incorporatedherein by reference.

TNF antagonists suitable for compositions, combination therapy,co-administration, devices and/or methods of the present inventioninclude, but are not limited to, anti-TNF antibodies (such as, Remicade(Infliximab) or Humira (adalimumab)) for example, or, antigen-bindingfragments thereof, and receptor molecules which bind specifically to TNF(such as, for example, Enbrel (Etanercept)); compounds which preventand/or inhibit TNF synthesis, TNF release or its action on target cells,such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g,pentoxifylline and rolipram), A2b adenosine receptor agonists and A2badenosine receptor enhancers; compounds which prevent and/or inhibit TNFreceptor signalling, such as mitogen activated protein (MAP) kinaseinhibitors; compounds which block and/or inhibit membrane TNF cleavage,such as metalloproteinase inhibitors; compounds which block and/orinhibit TNF activity, such as angiotensin converting enzyme (ACE)inhibitors (e.g., captopril); and compounds which block and/or inhibitTNF production and/or synthesis, such as MAP kinase inhibitors.

For clarification, a “tumor necrosis factor antibody,” “TNF antibody,”“TNF antibody,” or fragment and the like decreases, blocks, inhibits,abrogates or interferes with TNF activity in vitro, in situ and/orpreferably in vivo. For example, a suitable TNF human antibody of thepresent invention can bind TNFα and includes anti-TNF antibodies,antigen-binding fragments thereof, and specified mutants or domainsthereof that bind specifically to TNFα. A suitable TNF antibody orfragment can also decrease block, abrogate, interfere, prevent and/orinhibit TNF RNA, DNA or protein synthesis, TNF release, TNF receptorsignaling, membrane TNF cleavage, TNF activity, TNF production and/orsynthesis.

The foregoing and other useful combination therapies will be understoodand appreciated by those of skill in the art. Potential advantages ofsuch combination therapies include the ability to use less of each ofthe individual active ingredients to minimize toxic side effects,synergistic improvements in efficacy, improved ease of administration oruse and/or reduced overall expense of compound preparation orformulation.

As used herein, the terms “animal”, “subject” and “patient”, include,but are not limited to, a cow, monkey, horse, sheep, pig, chicken,turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human(preferably, a human).

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more solvent molecules toone of the compounds of formula (I). The term solvate includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “pre-osteoclast cell” is a cell capable offorming an osteoclast cell upon differentiation and/or fusion andincludes without limitation, circulating monocytes and tissuemacrophages (N. Kurihara et al., Endocrinology 126: 2733-41 (1990)).Without wishing to be bound by theory, pre-osteoclasts are converted toactivated osteoclasts in a process thought to involve two factorsproduced by pre-osteoblasts, M-CSF and ODF. These factors activatecertain genes that are needed for the conversion of a pre-osteoclastinto an osteoclast.

The biological activities of a heterocyclic compound can be evaluated bya number of cell-based assays. One of such assays can be conducted usingcells from human peripheral blood mononuclear cells (PBMC) or humanmonocytic cell line (THP-1). The cells are stimulated with a combinationof human interferon-γ (IFNγ) and lipopolysaccharide or a combination ofIFNγ and Staphylococcus aureus Cowan I in the presence of a testcompound. The level of inhibition of IL-12 production can be measured bydetermining the amount of p70 by using a sandwich ELISA assay withanti-human IL-12 antibodies. IC₅₀ of the test compound can then bedetermined. Specifically, PBMC or THP-1 cells are incubated with thetest compound. Cell viability was assessed using the bioreduction of MTS[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium](Promega, Madison, Wis.).

A compound can also be evaluated by animal studies. For example, one ofsuch studies involves the ability of a test compound to treat adjuvantarthritis (i.e., a IL-12 overproduction related disorder) in rats.

Responsiveness of a particular condition, disease or disorder tocompounds and compositions of this invention can be measured directly bycomparison against conventional drugs, or can be inferred based on anunderstanding of disease etiology and progression. There are a number ofcellular and bone resorption assay systems that are widely accepted inthe art as predictive of in vivo effects. As the bone resorption assayuses material that includes all bone cells, it is an ex vivo assay.Thus, the showing that a compound of this invention inhibits boneresorption in these assays is evidence of the clinical utility of thesefor treating or preventing conditions associated with excessive boneloss. Various scientific publications (such as Carano et al. J. Clin.Invest. 85: 456-461 (1990); Blair & Schlesinger, The Biology andPhysiology of the Osteoclast, CRC Press, Eds., Gay, C. V. and Rifkin, B.R., pp. 259-288 (1992); and Vaananen et al., J. Cell Biology 111:1305-1311 (1990)) support the fact that such assays are accepted asbeing predictive of in vivo activity. Furthermore, the in vitro effectsof Herbimycin A on bone resorption were shown to correlate with in vivoactivity (Yoneda et al., J. Clin. Invest. 91: 2791-95 (1993)).

Without further elaboration, it is believed that the above descriptionhas adequately enabled the present invention. The following specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.All of the references and publications cited herein are herebyincorporated by reference in their entirety.

EXAMPLES Example 1 Preparation of Compound 1

The structures of compounds A-E referred to below are shown in Scheme 1above.

To a solution of 2,4,6-trichloropyridine (3.65 g, 20 mmol) in 20 mldioxane was added morpholine (1.75 ml, 20 mmol) and DIPEA (3.50 ml, 20mmol). The mixture was heated at 85° C. for 5 hours. After cooling toroom temperature, the reaction mixture was diluted with water andextracted with EtOAc (300 ml). The organic phase was dried (Na₂SO₄),filtered and evaporated in vacuo to afford a crude mixture of isomers Aand B, which were separated by flash chromatography (Hexane-EtOAc, 9:1).Compound A (2.38 g, 51%) eluted first followed by compound B (1.05 g,22.5%).

Analytical data for Compound A: ¹H-NMR (CDCl₃) δ (ppm), 6.66 (s, 1H),6.46 (s, 1H), 3.83-3.77 (m, 4H), 3.56-3.50 (m, 4H); ESMS clcd forC₉H₁₀Cl₂N₂O: 232.02. Found: 233.1 (M+H)⁺.

To a solution of 3,4-dimethoxyphenylethyl alcohol (1.10 g, 6.0 mmol) inanhydrous DMF (15 ml) at 0° C. under the nitrogen, was added NaH (0.32g, 8.0 mmol). The suspension was stirred for 0.5 hours at 0° C. thencompound A (1.40 g, 6.0 mmol) was added as a solid. The mixture waswarmed to room temperature and stirred for 12 hours. The reaction wasquenched by ice brine and extracted with EtOAc (200 ml). The organicphase was washed with brine, dried (Na₂SO₄), filtered and evaporated invacuo to afford a crude mixture of isomers C and D, which were separatedby flash chromatography, which were separated by flash chromatography(Hexane-EtOAc, 8:2). Compound C (0.550 g, 24%) eluted first followed bycompound D (1.25 g, 54,9%).

Analytical data for Compound C: ¹H-NMR (CDCl₃) δ (ppm), 6.81-6.79 (m,3H), 6.12 (s, 2H), 4.40 (t, J=7.2 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H),3.79 (t, J=4.8 Hz, 4H), 3.46 (t, J=4.8 Hz, 4H), 2.99 (t, J=7.2 Hz, 2H);ESMS clcd for C₁₉H₂₃ClN₂O₄: 378.13. Found: 379.1 (M+H)⁺.

To compound C (220 mg, 0.58 mmol) was added anhydrous hydrazine (3 ml).The mixture was heated at 130-145° C. for 6 h. and quenched by brine (2ml) and extracted with EtOAc (15 ml). The organic phase was washed withbrine (5 ml) and water (5 ml×2) and dried (Na₂SO₄). The solvent wasevaporated in vacuo to give a crude product E.

To a solution of compound E (200 mg, 0.53 mmol) and 3-indolecarboxaldehyde (78 mg, 0.53 mmol) in MeOH (5 ml) was added catalyticamount of acetic acid (1 drop). The reaction mixture was stirred at roomtemperature for 12 h and a white solid was precipitated. The resultingprecipitate was collected by filtration and washed with a minimal volumeof methanol to give (55 mg) ofN-{2-[2-(3,4-dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-4-yl}-N′-(1H-indol-3-ylmethylene)-hydrazine(compound 1) in 21% yield. Analytical data for compound 1: ¹H-NMR(CDCl₃) δ (ppm), 8.40-8.25 (m, 2H), 7.95 (s, 1H), 7.48 (s, 1H),7.42-7.36 (m, 2H), 7.32-7.22 (m, 2H), 6.83 (s, 3H), 5.96 (d, J=12 Hz,2H), 4.45 (t, J=7.5 Hz, 2H), 3.90-3.80 (m, 10H), 3.54-3.45 (m, 4H), 3.04(t, J=7.5 Hz, 2H); ESMS calculated for C₂₈H₃₁N₅O₄: 501.24. Found: 502.3(M+H)⁺.

Example 2 Preparation of Compound 2

Compound 2,N-{6-[2-(3,4-dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(1H-indol-3-ylmethylene)-hydrazine,was prepared in a manner similar to that described for compound 1.Analytical data for compound 2: ¹H-NMR (CDCl₃) δ (ppm), 8.26-8.40 (m2H), 7.98 (s, 1H), 7.79 (s, 1H), 7.44-7.34 (m, 2H), 7.30-7.22 (m, 2H),6.83 (s, 3H), 6.47 (s, 1H), 5.66 (s, 1H), 4.40 (t, J=7.2 Hz, 2H),3.90-3.82 (m, 10H), 3.38-3.30 (m, 4H), 3.02 (t, J=6.3 Hz, 2H); ESMS clcdfor C₂₈H₃₁N₅O₄: 501.24. Found: 502.3 (M+H)⁺.

Example 3 Preparation of Compound 3

Compound 3,N-{4-[2-(3,4-dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-N′-(1H-indol-3-ylmethylene)-hydrazine,was prepared in a manner similar to that described for compound 1.Analytical data for compound 3: ¹H-NMR (CDCl₃) δ (ppm), 8.33 (d, J=7.8Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.40-7.12 (m, 4H),6.88-6.80 (m, 3H), 6.43 (s, 1H), 5.64 (s, 1H), 4.29 (t, J=6.9 Hz, 2H),3.86 (s, 6H), 3.80-3.75 (m, 4H), 3.43-3.39 (m, 4H), 3.09 (t, J=7.2 Hz,2H); ESMS clcd for C₂₈H₃₁N₅O₄: 501.24. Found: 502.3 (M+H)⁺.

Example 4 Preparation of Compound 4

A 25 mL round bottom flask was dried and charged with palladium acetate(10 mg, 0.05 mmol), binap (35 mg, 0.05 mmol) and toluene (8 mL). Theflask and its contents were flushed with nitrogen for 5 minutes andstirred under nitrogen for an additional 10 minutes. To a dried 50 mL ofround bottom flask was added cesium carbonate (0.88 g, 2.7 mmol),5-amino-2,3-dimethylindole (100 mg, 0.65 mmol),4-{2-chloro-6-[2-(3,4-dimethoxy-phenyl)-pyridin-4-yl}morpholine (200 mg,0.54 mmol), and toluene (12 mL) followed by the palladium/binap solutionprepared above. The resulting mixture was flushed with nitrogen for 5min. and heated at reflux under niteogen for 4 hours. Thereactionmixture was cooled to room temperature, then concentrated. The cruderesidue was purified by flash column chromatography (1:4 Ethylacetate/Hexane) to afford 84 mg (yield 32%) of compound 4,{6-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-(2,3-dimethyl-1H-indol-5-yl)-amine.

Analytical data for compound 4: ¹H NMR (CDCl₃): δ (ppm) 7.69 (s, 1H);7.40 (s, 1H); 7.20 (d, J=8.0 Hz, 1H); 7.02 (d, J=8.0 Hz, 2H); 6.82 (s,2H); 6.16 (s, 1H); 5.72 (s, 1H); 5.59 (s, 1H); 4.44 (t, J=6.0 Hz, 2H);3.89 (s, 6H); 3.72 (m, 4H); 3.12 (m, 4H); 3.02 (t, J=6.0 Hz, 2H); 2.36(s, 3H); 2.16 (s, 3H). ESMS calcd (C₂₇H₃₂N₄O₄): 502.3. found: 503.5(M+H)⁺.

Example 5 Preparation of Compound 5

Compound 5,N-{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine,was prepared in a manner similar to that described for compound 1.Analytical data for compound 5: ¹H NMR (CDCl₃): δ (ppm) 8.08 (s, 1H);7.95 (s, 1H); 7.66 (s, 1H); 7.43 (m, 2H); 7.27 (m, 1H); 7.15 (d, J=6.0Hz. 1H); 6.84 (d, J=6.0 Hz, 3H); 6.36 (d, J=3.0 Hz, 1H); 5.66 (d, J=3.0Hz, 1H); 4.25 (t, J=6.0 Hz, 2H); 3.88 (m, 10H); 3.40 (t, J=6.0 Hz, 4H);3.07 (t, J=6.0 Hz, 2H); 2.38 (s, 3H). ESMS calcd (C₂₇H₃₂N₄O₄): 476.2.found: 477.5 (M+H)⁺.

Example 6 Preparation of Compound 6

Compound 6,N-{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-4-yl}-N′-(3-methyl-benzylidene)-hydrazine,was prepared in a manner similar to that described for compound 1.Analytical data for compound 6: ¹H NMR (CDCl₃): δ (ppm) 7.65 (m, 2H);7.45 (m, 2H); 7.27 (m, 1H); 7.16 (m, 1H); 6.82 (s, 2H); 5.95 (s, 1H);5.89 (s, 1H); 4.42 (t, J=6.0 Hz, 2H); 3.86 (m, 10H); 3.31 (t, J=6.0 Hz,4H); 3.00 (t, J=6.0 Hz, 2H); 2.39 (s, 3H). ESMS calcd (C₂₇H₃₂N₄O₄):476.2. found: 477.5 (M+H)⁺.

Example 7 Preparation of Compound 7

Compound 7,N-{6-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-4-morpholin-4-yl-pyridin-2-yl}-N′-(3-methyl-benzylidene)-hydrazine,was prepared in a manner similar to that described for compound 1.Analytical data for compound 7: ¹H NMR (CDCl₃): δ (ppm) 7.95 (s, 1H);7.67 (s, 1H); 7.45 (m, 2H); 7.27 (m, 1H); 7.15 (m, 1H); 6.82 (m, 2H);6.40 (d, J=3.0 Hz, 1H); 5.66 (d, J=3.0 Hz, 1H); 4.37 (t, J=6.0 Hz, 2H);3.86 (m, 10H); 3.31 (t, J=6.0 Hz, 4H); 3.00 (t, J=6.0 Hz, 2H); 2.39 (s,3H). ESMS calcd (C₂₇H₃₂N₄O₄): 476.2. found: 477.5 (M+H)⁺.

Example 8 Preparation of Compound 8

Compound 8,{2-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-4-yl}-(2,3-dimethyl-1H-indol-5-yl)-amine,was prepared in a manner similar to that described for compound 4.Analytical data for compound 8: ¹H NMR (CDCl₃): δ (ppm) 7.74 (s, 1H);7.20 (d, J=9.0 Hz, 2H); 6.94 (m, 1H); 6.78 (m, 2H); 5.82 (s, 1H); 5.62(m, 2H); 4.36 (t, J=6.0 Hz, 2H); 3.76 (m, 10H); 3.36 (t, J=6.0 Hz, 4H);2.97 (t, J=6.0 Hz, 2H); 2.36 (s, 3H); 2.18 (s, 3H). ESMS calcd(C₂₇H₃₂N₄O₄): 502.3. found: 503.5 (M+H)⁺.

Example 9 Preparation of Compound 9

Compound 9,{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-(2,3-dimethyl-1H-indol-5-yl)-amine,was prepared in a manner similar to that described for compound 4.Analytical data for compound 9: ¹H NMR (CDCl₃): δ (ppm) 7.78 (s, 1H);7.39 (s, 1H); 7.16 (d, J=9.0 Hz, 1H); 6.98 (m, 1H); 6.78 (m, 2H); 6.25(s, 1H); 5.67 (s, 1H); 5.57 (m, 1H); 4.10 (t, J=6.0 Hz, 2H); 3.86 (m,10H); 3.36 (t, J=6.0 Hz, 4H); 2.94 (t, J=6.0 Hz, 2H); 2.34 (s, 3H); 2.16(s, 3H). ESMS calcd (C₂₇H₃₂N₄O₄): 502.3. found: 503.5 (M+H)⁺.

Example 10 Preparation of Compound 10

Compound 10,{4-[2-(3,4-Dimethoxy-phenyl)-ethoxy]-6-morpholin-4-yl-pyridin-2-yl}-m-tolyl-amine,was prepared in a manner similar to that described for compound 4.Analytical data for compound 9: ¹H NMR (CDCl₃): 6 (ppm) 7.18 (m, 1H);7.09 (m, 2H); 6.80 (m, 4H); 6.24 (s, 1H); 5.84 (s, 1H); 5.62 (s, 1H);5.72 (s, 1H); 5.59 (s, 1H); 4.11 (t, J=6.0 Hz, 2H); 3.86 (s, 6H); 3.78(t, J=6.0 Hz, 4H); 3.44 (t, J=6.0 Hz, 2H); 3.0 (t, J=6.0 Hz, 2H); 2.32(s, 3H). ESMS calcd (C₂₇H₃₂N₄O₄): 449.2. found: 450.5 (M+H)⁺.

Example 11 Preparation of Compound 11

Compound 11(3-(2-{2-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyridin-4-yloxy}-ethyl)oxazolidin-2-one)was prepared as follows:

To a solution of 3-(2-hydroxyethyl)-oxazolidin-2-one (0.66 g, 5.0 mmol)in anhydrous DMF (10 ml) at 0° C. under nitrogen was added NaH (0.240 g,6.0 mmol). The suspension was stirred for 0.5 h at 0° C. and solidcompound A 4-(4,6-dichloro-pyridin-2-yl)-morpholine (see Example 1, 1.17g, 5.0 mmol) was added. After the mixture warmed to room temperature andstirred for 12 h, the reaction was quenched with ice brine and extractedwith EtOAc (200 ml). The organic phase was washed with brine, dried(Na₂SO₄), filtered and evaporated in vacuo. The isomers F and G wereseparated by flash chromatography (Hexane EtOAc, 3:1). ESMS clcd for Fand G C₁₄H₁₈ClN₃O₄: 327.10. Found: 328.2 (M+H).

A mixture of compound G3-[2-(2-chloro-6-morpholin-4-yl-pyridin-4-yloxy)-ethyl]-oxazolidin-2-one(165 mg, 0.50 mmol), t-butylcarbazate (135 mg, 1.0 mmol), Pd₂(dba)₃ (20mg, 0.02 mmol), DPPF (35 mg, 0.06 mmol), Cs₂CO₃ (325 mg, 1.0 mmol) andtoluene (3 ml) in a sealed tube under the nitrogen, was heated at 100°C. for 16 h. The reaction mixture was allowed to cool to roomtemperature, diluted with dichloromethane, filtered and concentrated.The crude product was then purified by flash column chromatography onsilica gel (Hexane EtOAc, 1:1), to give compound H,N-{6-morpholi-4-yl-4-[2-(2-oxo-oxozolidin-3-yl)-ethoxy]-pyridin-yl}-hydrazinecarboxylicacid tert-butyl ester (130 mg, 61%).

To a solution of compound H (120 mg, 0.28 mmol) in anhydrous CH₂Cl₂ (3ml) was added trifluoroacetic acid (TFA) (2 ml) and the mixture washeated at 50° C. for 5 h. The solvent was evaporated to give crude3-[2-(2-hydrazino-6-morpholin-4-yl-pyridin-4-yloxy)-ethyl]-oxazolidin-2-onetrifluoro-acetic salt. The crude product was then dissolved in methanol(4 ml) and to the solution was added m-tolualdehyde (40 mg, 0.33 mmol)and acetic acid (1 drop). The reaction mixture was stirred at roomtemperature for 12 h; a white solid was precipitated. The resultingprecipitate was collected by filtration and washed with a small amountof methanol to give 85 mg (71%)3-(2-{2-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyridin-4-yloxy}-ethyl)oxazolidin-2-one.

¹H-NMR (CDCl₃) δ (ppm), 7.82 (s, 1H), 7.48-7.45 (m, 2H), 7.30-7.25 (m,2H), 7.17-7.12 (m, 1H), 6.36 (d, J=1.5 Hz, 1H) 5.61 (d, J=1.8 Hz, 1H),4.35 (t, J=6.6 Hz, 2H), 4.27 (t, J=4.8 Hz, 2H), 3.82-3.74 (m, 6H), 3.70(t, J=4.8 Hz, 2H), 3.42 (t, J=4.8 Hz, 4H), 2.39 (s, 3H).

ESMS calculated for C₂₂H₂₇N₅O₄: 425.21. Found: 426.1 (M+H)⁺.

Example 12 Synthesis of(N-[3,5-Difluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-N′-(3-methyl-benzylidene)-hydrazine)

4-(2,3,5,6-Tetrafluoro-pyridin-4-yl)-morpholine: Pentafluoropyridine(3.4 g; 20 mmol) was dissolved in dichloromethane (50 mL) and chilled inan ice bath. To the solution was added morpholine (3.48 g; 40 mmol) andthe reaction was allowed to warm to room temperature with stirringovernight. The organic phase was washed with saturated ammonium chloridesolution (2×20 mL), dried over magnesium sulfate, evaporated, andpurified by column chromatography to give4-(2,3,5,6-tetrafluoro-pyridin-4-yl)-morpholine.

4-[2,3,5-Trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine:4-(2,3,5,6-Tetrafluoro-pyridin-4-yl)-morpholine (2.36 g; 10 mmol) wasdissolved in tetrahydrofuran (50 mL). To the solution was added4-(2-hydroxyethyl)-morpholine (1.57 g; 12 mmol) followed by sodiumhydride (288 mg; 12 mmol), and it was stirred overnight. The solvent wasthen evaporated, and the solid was purified by column chromatography togive4-[2,3,5-trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine(3.3 g).

Compound 12:4-[2,3,5-Trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine(1.2 g; 3.5 mmol) and hydrazine (2 g) were added to dioxane (10 mL) andheated to 100° C. for six hours. The solvent was evaporated, and theresidue was dissolved in dichloromethane (20 mL) and washed with a 10%sodium carbonate solution (2 mL). It was dried over magnesium sulfate,and evaporated, to give crude[3,5-Difluoro-4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine. The crude product was then dissolvedin ethanol. To the solution was added one drop of acetic acid, andm-tolylaldehyde (600 mL; 5 mmol) and it was heated at 60° C. overnight.The solvent was then evaporated, and the residue was purified by columnchromatography to give Compound 12 (850 mg). Theoretical Mass Ion:461.1; observed MH⁺ peak: 462.1.

Example 13 Synthesis ofN-[3,5-Difluoro-2-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-N′-(3-methyl-benzylidene)-hydrazine

N-(3-Methyl-benzylidene)-N′-(2,3,5,6-tetrafluoro-pyridin-4-yl)-hydrazine:Pentafluoropyridine (3.4 g; 20 mmol) was dissolved in dichloromethane(50 mL) and chilled in an ice bath. To the solution was added hydrazine(640 mg; 22 mmol) and it was stirred overnight. The solvent wasevaporated, and the residue was dissolved in dichloromethane (50 mL) andwashed with a 10% sodium carbonate solution (5 mL). It was dried overmagnesium sulfate, and evaporated, to give crude2,3,5,6-tetrafluoro-pyridin-4-yl-hydrazine. The crude product was thendissolved in ethanol. To the solution was added one drop of acetic acid,and m-tolylaldehyde (1.45 g; 12 mmol) and it was heated at 60° C.overnight. The resulting precipitate was filtered and dried to giveN-(3-methyl-benzylidene)-N′-(2,3,5,6-tetrafluoro-pyridin-4-yl)-hydrazine(2.2 g).

N-(3-Methyl-benzylidene)-N′-[2,3,5-trifluoro-6-(2-piperidin-1-yl-ethoxy)-pyridin-4-yl]-hydrazine:N-(3-methyl-benzylidene)-N′-(2,3,5,6-tetrafluoro-pyridin-4-yl)-hydrazine(2.2 g; 7.8 mmol) was dissolved in tetrahydrofuran (100 mL) and to thesolution was added 4-(2-hydroxyethyl)-morpholine (1.3 g; 10 mmol)followed by sodium hydride (480 mg; 20 mmol). The solution was stirredat reflux for 24 hours. The solvent was then evaporated, and the solidwas purified by column chromatography to giveN-(3-methyl-benzylidene)-N′-[2,3,5-trifluoro-6-(2-piperidin-1-yl-ethoxy)-pyridin-4-yl]-hydrazine(830 mg).

Compound 13:N-(3-methyl-benzylidene)-N′-[2,3,5-trifluoro-6-(2-piperidin-1-yl-ethoxy)-pyridin-4-yl]-hydrazine(784 mg; 2 mmol) was dissolved in neat morpholine (2 mL) and heated in asealed tube using microwave heating to 150° C. for ten minutes. Thecrude solution was purified by column chromatography to give Compound 13(550 mg). Theoretical Mass Ion: 461.1; observed MH⁺ peak: 462.1.

Examples 14-21

Additional compounds according to the invention were prepared by methodssimilar to the methods of Examples 1-13, supra.

Compound 14N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

ESMS calculated for C₂₃H₃₁N₅O₃: 425.24. Found: 426.1 (M+H)⁺.

Compound 15

{2-[N′-(3-Methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyridin-4-yl}-(2-morpholin-4-yl-ethyl)-amine

ESMS calculated for C₂₃H₃₁N₅O₃: 425.24. Found: 426.2 (M+H)⁺.

Compound 16

N-(1H-Indol-3-ylmethylene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

ESMS calculated for C₂₄H₃₀N₆O₃: 450.24. Found: 451.1 (M+H)⁺.

Compound 17

N-Methyl-N′-(3-methyl-benzylidene)-N-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

ESMS calculated for C₂₄H₃₃N₅O₃: 439.26. Found: 440.2 (M+H)⁺.

Compound 18

3-(2-{2-[N′-(3-Methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyridin-4-yloxy}-ethyl)-oxazolidin-2-one

ESMS calculated for C₂₂H₂₇N₅O₄: 425.21. Found: 426.1 (M+H)⁺.

Compound 19

N-Furan-3-ylmethylene-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine

ESMS calculated for C₂₀H₂₇N₅O₄: 401.21. Found: 402.1 (M+H)⁺.

Compound 20

4-Methyl-2-{[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazonomethyl}-phenylamine

ESMS calculated for C₂₃H₃₂N₆O₃: 440.25. Found: 4410.1 (M+H)⁺.

Compound 21

N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-1-oxy-pyridin-2-yl]-hydrazine

ESMS calculated for C₂₃H₃₁N₅O₄: 441.24. Found: 442.1 (M+H)⁺.

Example 22 In Vitro Assays

Reagents. Staphylococcus aureus Cowan I (SAC) is obtained fromCalbiochem (La Jolla, Calif.), and lipopolysaccharide (LPS, Serratiamarscencens) is obtained from Sigma (St. Louis, Mo.). Human and mouserecombinant IFNγ are purchased from Boehringer Mannheim (Mannheim,Germany) and Pharmingen (San Diego, Calif.), respectively.

Human In Vitro Assay. Human PBMC were isolated by centrifugation usingFicoll-Paque (Pharmacia Biotech, Uppsala, Sweden) and prepared in RPMImedium supplemented with 10% fetal calf serum (FCS), 100 U/mLpenicillin, and 100 μg/mL streptomycin. PBMC were plated in wells of a96-well plate at a concentration of 5×10⁵ cells/well, and primed byadding IFNγ (30 U/mL) for 22 h and stimulated by adding LPS (1 μg/mL),or by adding IFNγ (100 U/mL) and then stimulated by adding SAC (0.01%).A test pyridine compound was dissolved in DMSO, and added to wells ofthe 96-well plate. The final DMSO concentration was adjusted to 0.25% inall cultures, including the compound-free control. Human THP-1 cellswere plated in wells, primed by adding IFNγ (100 U/mL) for 22 h andstimulated by adding SAC (0.025%) in the presence of differentconcentrations of the pyridine compound. Cell-free supernatants weretaken 18 h later for measurement of cytokines. Cell viability wasassessed using the bioreduction of MTS. Cell survival was estimated bydetermining the ratio of the absorbance in compound-treated groupsversus compound-free control.

The supernatant was assayed for the amount of IL-12p40, IL-12p70, orIL-10 by using a sandwich ELISA with anti-human antibodies, i.e., aHuman IL-12 p40 ELISA kit from R&D Systems (Berkeley, Calif.), and aHuman IL-12 p70 or IL-10 ELISA kit from Endogen (Cambridge, Mass.).Assays were based on the manufacturer's instructions.

Murine In Vitro Assay. Balb/c mice (Taconic, Germantown, N.Y.) wereimmunized with Mycobacterium tuberculosis H37Ra (Difco, Detroit, Mich.).The splenocytes were harvested 5 days and prepared in RPMI mediumsupplemented with 10% FCS and antibiotics in a flat bottom 96-well platewith 1×10⁶ cells/well. The splenocytes were then stimulated with acombination of IFNγ (60 ng/mL) and SAC (0.025%) [or LPS (20 μg/mL)] inthe presence of a test compound. Cell-free supernatants were taken 24 hlater for the measurement of cytokines. The preparation of compound andthe assessment of cell viability were carried out as described above.Mouse IL-12 p70, IL-10, IL-1β, and TNFα were measured using ELISA kitsfrom Endogen, according to the manufacturer's instructions.

The biological activities of pyridine compounds were tested on humanPBMC or THP-1 cells. IC⁵⁰ data is shown in Table 1 below.

TABLE 1 Compound IC⁵⁰ 1 10 nM 2 5 nM 3 0.8 μM 4 197 nM 5 2 μM 6 5 nM 714.1 nM 8 28 nM 9 350 nM 10 5 μM 11 927 nM 12 >1000 nM 13 148 nM 14 25nM 15 714.8 nM 16 36.6 nM 17 14.2 nM 18 927 nM 19 5000 nM 20 11.4 nM 2186 nM

Example 23 In Vivo Assays

Treatment of adjuvant arthritis in rats: Adjuvant arthritis (AA) can beinduced in rats, and the ability of a compound of the invention toprevent, reduce, or reverse the induced arthritis can be measured (see,e.g., Example 24, infra). For example, AA can be induced by theintracutaneous injection of 0.1 mL of a 10 mg/mL bacterial suspensionmade from ground, heat-killed Mycobacterium tuberculosis H37Ra suspendedin incomplete Freund's adjuvant. Rats are then given a test compound,and the development of polyarthritis is monitored daily by macroscopicinspection and assignment of an arthritis index to each animal, e.g.,during the critical period (days 10 to 25 post-immunization).

Treatment of Crohn's disease in dinitrobenzene sulfonic acid-inducedinflammatory bowel syndrome model rats: Wistar derived male or femalerats weighing 200±20 g and fasted for 24 hours are used. Distal colitisis induced by intra-colonic instillation of 2,4-dinitrobenzene sulfonicacid (DNBS, 25 mg in 0.5 mL ethanol 30%) after which air (2 mL) isgently injected through the cannula to ensure that the solution remainedin the colon. A test compound and/or vehicle is administered orally 24and 2 hours before DNBS instillation and then daily for 5 days. Onecontrol group is similarly treated with vehicle alone while the other istreated with vehicle plus DNBS. The animals are sacrificed 24 hoursafter the final dose of test compound administration and each colon isremoved and weighed. Colon-to-body weight ratio is then calculated foreach animal according to the formula: Colon (g)/BW×100. The “Net”increase in ratio of Vehicle-control+DNBS group relative toVehicle-control group is used as a base for comparison with testsubstance treated groups and expressed as “% Deduction.”

Treatment of Crohn's disease in CD4⁺CD45Rb^(high) T cell-reconstitutedSCID colitis model mice: Spleen cells are prepared from normal femaleBALB/c mice. For cell purification, the following anti-mouse antibodiesare used to label non-CD4⁺ T cells: B220 (RA3-6B2), CD11b (M1/70), andCD8α (53-6.72). All antibodies are obtained from BioSource (Camarillo,Calif.). M450 anti-rat IgG-coated magnetic beads (Dynal, Oslo, Norway)are used to bind the antibodies and negative selection is accomplishedusing an MPC-1 magnetic concentrator. The enriched CD4⁺ cells are thenlabeled for cell sorting with FITC-conjugated CD45RB (16A, Pharmingen,San Diego, Calif.) and PE-conjugated CD4 (CT-CD4, Caltag, Burlingame,Calif.). CD4⁺ CD45RB^(high) cells are operationally defined as the upper40% of CD45Rb-staining CD4⁺ cells and sorted under sterile conditions byflow cytometry. Harvested cells are resuspended at 4×10⁶/mL in PBS andinjected 100 μL intraperitoneally into female C.B-17 SCID mice. Pyridinecompounds of this invention and/or vehicle is orally administered once aday, 5 days per week, starting the day following the transfer. Thetransplanted SCID mice are weighed weekly and their clinical conditionwas monitored.

Colon tissue samples are fixed in 10% buffered formalin and embedded inparaffin. Sections (4 μm) collected from ascending, transverse, anddescending colon are cut and stained with hematoxylin and eosin. Theseverity of colitis is determined based on histological examination ofthe distal colon sections, whereby the extent of colonic inflammation isgraded on a scale of 0-3 in each of four criteria: crypt elongation,cell infiltration, depletion of goblet cells, and the number of cryptabscesses.

LP lymphocytes are isolated from freshly obtained colonic specimens.After removal of payer's patches, the colon is washed in Ca/Mg-freeHBSS, cut into 0.5 cm pieces and incubated twice in HBSS containing EDTA(0.75 mM), DTT (1 mM), and antibiotics (amphotericin 2.5 μg/mL,gentamicin 50 μg/mL from Sigma) at 37° C. for 15 min. Next, the tissueis digested further in RPMI containing 0.5 mg/mL collagenase D, 0.01mg/mL DNase I (Boehringer Manheim), and antibiotics at 37° C. LP cellsare then layered on a 40-100% Percoll gradient (Pharmacia, Uppsala,Sweden), and lymphocyte-enriched populations are isolated from the cellsat the 40-100% interface.

To measure cytokine production, 48-well plates are coated with 10 μg/mLmurine anti-CD3ε antibody (145-2C11) in carbonate buffer (PH 9.6)overnight at 4° C. 5×10⁵ LP cells are then cultured in 0.5 ml ofcomplete medium in precoated wells in the presence of 1 μg/mL solubleanti-CD28 antibody (37.51). Purified antibodies are obtained fromPharmingen. Culture supernatants are removed after 48 h and assayed forcytokine production. Murine IFNγ is measured using an ELISA kit fromEndogen (Cambridge, Mass.), according to the manufacturer'sinstructions.

Example 24

Human peripheral blood mononuclear cells (PBMC) are isolated fromhealthy donor blood. The cells are seeded in multi-well plates at7.5×10⁵ cells/ml in RPMI 1640 medium including 10% FBS. Osteoclastformation is induced with 20 ng/ml of recombinant human receptoractivator of NF-kB-ligand (RANKL) and 10 ng/ml of human M-CSF in thepresence of various doses of test compounds. After 48 hours of culture,RANKL and M-CSF is replenished and further cultured for 2 days. Then,the cultured cells are stained for tartrate-resistant acid phosphatase(TRAP). Osteoclasts are identified as TRAP-positive cells with more than3 nuclei. Total cell viability is assessed by CCK-8 assay (Dojindo,Gaithersburg, Md.) with 24 hour incubation.

Example 25 In Vivo Adjuvant Arthritis Assay

Treatment of adjuvant arthritis in rats: Adjuvant arthritis (AA) wasinduced in female Lewis rats by the intracutaneous injection (base ofthe tail) of 0.1 mL of a 10 mg/mL bacterial suspension made from ground,heat-killed Mycobacterium tuberculosis H37Ra suspended in incompleteFreund's adjuvant. Rats were given a test compound orally once a day for7 days (day 7-14), starting day 7 after mycobacterium induction. Thedevelopment of polyarthritis was monitored daily by macroscopicinspection and assignment of an arthritis index to each animal, duringthe critical period (days 10 to 25 post-immunization).

The intensity of polyarthritis was scored according to the followingscheme: (a) Grade each paw from 0 to 3 based on erythema, swelling, anddeformity of the joints: 0 for no erythema or swelling; 0.5 if swellingis detectable in at least one joint; 1 for mild swelling and erythema; 2for swelling and erythema of both tarsus and carpus; and 3 for ankylosisand bony deformity. Maximum score for all 4 paws was thus 12. (b) Gradefor other parts of the body: for each ear, 0.5 for redness and another0.5 if knots are present; 1 for connective tissue swelling (saddlenose); and 1 for the presence of knots or kinks in the tail. The highestpossible arthritic index was 16.

Experiments with the AA model were repeated four times. Oraladministration of a pyridine compound of this invention(N-(3-Methyl-benzylidene)-N′-[4-morpholin-4-yl-6-(2-morpholin-4-yl-ethoxy)-pyridin-2-yl]-hydrazine,Compound 14) reproducibly reduced the arthritic score and delayed thedevelopment of polyarthritis in a dose-dependent manner (see FIG. 1).The arthritis score used in this model was a reflection of theinflammatory state of the structures monitored and the results thereforeshows the ability of the test compound to provide relief for this aspectof the pathology.

OTHER EMBODIMENTS

All of the features, specific embodiments and particular substituentsdisclosed herein may be combined in any combination. Each feature,embodiment or substituent disclosed in this specification may bereplaced by an alternative feature, embodiment or substituent servingthe same, equivalent, or similar purpose. In the case of chemicalcompounds, specific values can be combined in any combination resultingin a stable structure. Furthermore, specific values (whether preferredor not) for substituents in one type of chemical structure may becombined with values for other substituents (whether preferred or not)in the same or different type of chemical structure. Thus, unlessexpressly stated otherwise, each feature, embodiment or substituentdisclosed is only an example of a generic series of equivalent orsimilar features feature, embodiments or substituents.

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

1.-68. (canceled)
 69. A method for treating an interleukin-12overproduction-related disorder, comprising administering to a subjectin need thereof an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof wherein,

R₂ and R₄ are, independently, H, an optionally substituted alkyl anoptionally substituted alkylcarbonyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c), —NR^(k)C(O)R^(c),—C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c), —NR^(k)C(S)R^(c), —C(NR)R^(c),—OC(NR)R^(c), —SC(NR)R^(c), —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c),—NR^(k)SO₂R^(c), —OS(O)₂R^(c), —OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo,haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, anoptionally substituted alkylcarbonylalkyl, an optionally substitutedcyclyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aryl an optionally substituted aralkyl, an optionallysubstituted heteroaryl, an optionally substituted heteroaralkyl, orisothionitro; or R₂ and R₄ taken together are ═O, ═S, or ═NR; R₃ is anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, or an optionallysubstituted heteroaryl; R₅ is —H, alkyl, alkylcarbonyl, halo, nitro,nitroso, cyano, azido, isothionitro, —OR^(p) or —SR^(p); and R^(p) is—H, alkyl, or alkylcarbonyl; n, for each occurrence, is independently 0,1, 2, 3, 4, 5, 6 or 7; X is NH; Y is O; Z is N; W is O; G is absent; andone of Q, U and V is N, and the other two are each CR^(g) and eachCR^(g) may be the same or different; wherein: R, for each occurrence, isindependently H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, an optionally substituted cyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,—C(O)R^(c), —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl, nitro, cyano,haloalkyl, aminoalkyl, or —S(O)₂R^(c); R^(a) is H and R^(b) isoptionally substituted aryl; R^(c) is H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, haloalkyl, —OR^(k), —SR^(k),—NR^(h)R^(j), hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl,aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy; R^(g), for eachoccurrence, is independently, H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl,sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R^(c), —OC(O)R^(c),—SC(O)R^(c), —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),—NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),—NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c), —OS(O)₂R^(c),—OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo, aminoalkyl, mercaptoalkyl,cyano, nitro, nitroso, or azide; R^(h) and R^(j), for each occurrence,are independently H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl; orR^(h) and R^(j) taken together with the N to which they are attached isan optionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, or an optionally substituted heteroaryl; and R^(k),for each occurrence, is independently H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, oran optionally substituted heteroaryl.
 70. The method of claim 69,wherein the disorder is selected from the group consisting of multiplesclerosis, sepsis, myasthenia gravis, autoimmune neuropathies,Guillain-Barré syndrome, autoimmune uveitis, autoimmune hemolyticanemia, pernicious anemia, autoimmune thrombocytopenia, temporalarteritis, anti-phospholipid syndrome, vasculitides, Wegener'sgranulomatosis, Behcet's disease, psoriasis, psoriatic arthritis,dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease,ulcerative colitis, interstitial pulmonary fibrosis, myelofibrosis,hepatic fibrosis, myocarditis, thyroditis, primary biliary cirrhosis,autoimmune hepatitis, immune-mediated diabetes mellitus, Grave'sdisease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis,autoimmune disease of the adrenal gland; rheumatoid arthritis, juvenilerheumatoid arthritis, systemic lupus erythematosus, scleroderma,polymyositis, dermatomyositis, spondyloarthropathies, ankylosingspondylitis, Sjogren's syndrome and graft-versus-host disease.
 71. Themethod of claim 70, wherein the disorder is rheumatoid arthritis,sepsis, Crohn's disease, multiple sclerosis, psoriasis, orimmune-mediated diabetes mellitus. 72-74. (canceled)
 75. A method fortreating or preventing disorders associated with excessive bone loss,the method comprising administering to a subject in need thereof aneffective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof wherein,

R₂ and R₄ are, independently, H, an optionally substituted alkyl anoptionally substituted alkylcarbonyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c), —NR^(k)C(O)R^(c),—C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c), —NR^(k)C(S)R^(c), —C(NR)R^(c),—OC(NR)R^(c), —SC(NR)R^(c), —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c),—NR^(k)SO₂R^(c), —OS(O)₂R^(c), —OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo,haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, anoptionally substituted alkylcarbonylalkyl, an optionally substitutedcyclyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aryl an optionally substituted aralkyl, an optionallysubstituted heteroaryl, an optionally substituted heteroaralkyl, orisothionitro; or R₂ and R₄ taken together are ═O, ═S, or ═NR; R₃ is anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, or an optionallysubstituted heteroaryl; R₅ is —H, alkyl, alkylcarbonyl, halo, nitro,nitroso, cyano, azido, isothionitro, —OR^(p) or —SR^(p); and R^(p) is—H, alkyl, or alkylcarbonyl; n, for each occurrence, is independently 0,1, 2, 3, 4, 5, 6 or 7; X is NH; Y is O; Z is N; W is O; G is absent; andone of Q, U and V is N, and the other two are each CR^(g) and eachCR^(g) may be the same or different; wherein: R, for each occurrence, isindependently H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, an optionally substituted cyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,—C(O)R^(c), —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl, nitro, cyano,haloalkyl, aminoalkyl, or —S(O)₂R^(c); R^(a) is H and R^(b) isoptionally substituted aryl; R^(c) is H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, haloalkyl, —OR^(k), —SR^(k),—NR^(h)R^(j), hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl,aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy; R^(g), for eachoccurrence, is independently, H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl,sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R^(c), —OC(O)R^(c),—SC(O)R^(c), —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),—NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),—NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c), —OS(O)₂R^(c),—OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo, aminoalkyl, mercaptoalkyl,cyano, nitro, nitroso, or azide; R^(h) and R^(j), for each occurrence,are independently H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl; orR^(h) and R^(j) taken together with the N to which they are attached isan optionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, or an optionally substituted heteroaryl; and R^(k),for each occurrence, is independently H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, oran optionally substituted heteroaryl.
 76. The method of claim 75,wherein the disorder is periodontal disease, non-malignant bonedisorders, osteoporosis, Paget's disease of bone, osteogenesisimperfecta, fibrous dysplasia, and primary hyperparathyroidism, estrogendeficiency, inflammatory bone loss, bone malignancy, arthritis,osteopetrosis, hypercalcemia of malignancy (HCM), osteolytic bonelesions of multiple myeloma and osteolytic bone metastases of breastcancer, and metastatic cancers. 77-79. (canceled)
 80. A method ofinhibiting the production of IL-12 and/or inhibiting the production of acytokine that stimulates or facilitates the production of IL-12 (e.g.,IL-23 and IL-27) in a subject by administering to the subject aneffective amount of a compound formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof wherein,

R₂ and R₄ are, independently, H, an optionally substituted alkyl, anoptionally substituted alkylcarbonyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c), —NR^(k)C(O)R^(c),—C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c), —NR^(k)C(S)R^(c), —C(NR)R^(c),—OC(NR)R^(c), —SC(NR)R^(c), —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c),—NR^(k)SO₂R^(c), —OS(O)₂R^(c), —OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo,haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, anoptionally substituted alkylcarbonylalkyl, an optionally substitutedcyclyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aryl, an optionally substituted aralkyl, an optionallysubstituted heteroaryl, an optionally substituted heteroaralkyl, orisothionitro; or R₂ and R₄ taken together are ═O, ═S, or ═NR; R₃ is anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, or an optionallysubstituted heteroaryl; R₅ is —H, alkyl, alkylcarbonyl, halo, nitro,nitroso, cyano, azido, isothionitro, —OR^(p) or —SR^(p); and R^(p) is—H, alkyl, or alkylcarbonyl; n, for each occurrence, is independently 0,1, 2, 3, 4, 5, 6 or 7; X is NH; Y is O; Z is N; W is O; G is absent; andone of Q, U and V is N, and the other two are each CR^(g) and eachCR^(g) may be the same or different; wherein: R, for each occurrence, isindependently H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, an optionally substituted cyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,—C(O)R^(c), —OR^(k), —SR^(k), —NR^(h)R^(j), hydroxylalkyl, nitro, cyano,haloalkyl, aminoalkyl, or —S(O)₂R^(c); R^(a) is H and R^(b) isoptionally substituted aryl; R^(c) is H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, haloalkyl, —OR^(k), —SR^(k),—NR^(h)R^(j), hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl,aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy; R^(g), for eachoccurrence, is independently, H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl,sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R^(c), —OC(O)R^(c),—SC(O)R^(c), —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),—NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),—NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c),—OS(O)_(n)R^(c), —OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo, aminoalkyl,mercaptoalkyl, cyano, nitro, nitroso, or azide; R^(h) and R^(j), foreach occurrence, are independently H, an optionally substituted alkyl anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, an optionally substituted aryl an optionallysubstituted heteroaryl; or R^(h) and R^(j) taken together with the N towhich they are attached is an optionally substituted heterocyclyl, anoptionally substituted heterocycloalkyl, or an optionally substitutedheteroaryl; and R^(k), for each occurrence, is independently H, anoptionally substituted alkyl an optionally substituted alkenyl, anoptionally substituted alkynyl, an optionally substituted cyclyl, anoptionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, anoptionally substituted aryl or an optionally substituted heteroaryl. 81.The method of claim 80, wherein the cytokine that stimulates orfacilitates the production of IL-12 is IL-23 or IL-27.
 82. A method oftreating an inflammatory disorder in a subject in need of suchtreatment, the method comprising administering to the subject aneffective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, orprodrug thereof wherein,

R₂ and R₄ are, independently, H, an optionally substituted alkyl, anoptionally substituted alkylcarbonyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, —C(O)R^(c), —OC(O)R^(c), —SC(O)R^(c), —NR^(k)C(O)R^(c),—C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c), —NR^(k)C(S)R^(c), —C(NR)R^(c),—OC(NR)R^(c), —SC(NR)R^(c), —NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c),—NR^(k)SO₂R^(c), —OS(O)₂R^(c), —OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo,haloalkyl, aminoalkyl, mercaptoalkyl, cyano, nitro, nitroso, azide, anoptionally substituted alkylcarbonylalkyl, an optionally substitutedcyclyl, an optionally substituted cycloalkyl, an optionally substitutedheterocyclyl, an optionally substituted heterocycloalkyl, an optionallysubstituted aryl, an optionally substituted aralkyl, an optionallysubstituted heteroaryl, an optionally substituted heteroaralkyl, orisothionitro; or R₂ and R₄ taken together are ═O, ═S, or ═NR; R₃ is anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aryl, or an optionallysubstituted heteroaryl; R₅ is —H, alkyl, alkylcarbonyl, halo, nitro,nitroso, cyano, azido, isothionitro, —OR^(p) or —SR^(p); and R^(p) is—H, alkyl, or alkylcarbonyl; n, for each occurrence, is independently 0,1, 2, 3, 4, 5, 6 or 7; X is NH; Y is O; Z is N; W is O; G is absent; andone of Q, U and V is N, and the other two are each CR^(g) and eachCR^(g) may be the same or different; wherein: R, for each occurrence, isindependently H, an optionally substituted alkyl, an optionallysubstituted cycloalkyl, an optionally substituted cyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteroaralkyl,—C(O)R^(c), —OR^(k), —SR^(k), —NR^(k)R^(j), hydroxylalkyl, nitro, cyano,haloalkyl, aminoalkyl, or —S(O)₂R^(c); R^(a) is H and R^(b) isoptionally substituted aryl; R^(c) is H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl, anoptionally substituted heteroaryl, haloalkyl, —OR^(k), —SR^(k),—NR^(h)R^(j), hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl,aminoalkyl, sulfonylalkyl, sulfonylaryl, or thioalkoxy; R^(g), for eachoccurrence, is independently, H, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cyclyl, an optionally substituted cycloalkyl, anoptionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, haloalkyl, —OR^(k), —SR^(k), —NR^(h)R^(j),hydroxylalkyl, alkylcarbonylalkyl, mercaptoalkyl, aminoalkyl,sulfonylalkyl, sulfonylaryl, thioalkoxy, —C(O)R^(c), —OC(O)R^(c),—SC(O)R^(c), —NR^(k)C(O)R^(c), —C(S)R^(c), —OC(S)R^(c), —SC(S)R^(c),—NR^(k)C(S)R^(c), —C(NR)R^(c), —OC(NR)R^(c), —SC(NR)R^(c),—NR^(k)C(NR)R^(c), —SO₂R^(c), —S(O)R^(c), —NR^(k)SO₂R^(c), —OS(O)₂R^(c),—OP(O)R^(c)R^(c), —P(O)R^(c)R^(c), halo, aminoalkyl, mercaptoalkyl,cyano, nitro, nitroso, or azide; R^(h) and R^(j), for each occurrence,are independently H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cyclyl, an optionally substituted cycloalkyl, an optionallysubstituted heterocyclyl, an optionally substituted heterocycloalkyl, anoptionally substituted aralkyl an optionally substituted heteroaralkyl,an optionally substituted aryl, an optionally substituted heteroaryl; orR^(h) and R^(j) taken together with the N to which they are attached isan optionally substituted heterocyclyl, an optionally substitutedheterocycloalkyl, or an optionally substituted heteroaryl; and R^(k),for each occurrence, is independently H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cyclyl, an optionally substitutedcycloalkyl, an optionally substituted heterocyclyl, an optionallysubstituted heterocycloalkyl, an optionally substituted aralkyl, anoptionally substituted heteroaralkyl, an optionally substituted aryl oran optionally substituted heteroaryl. 83-89. (canceled)